View source for Penicillin

{{Short description|Group of antibiotics derived from Penicillium fungi}}
{{Other uses}}
{{Pp-semi-indef}}
{{Pp-move-indef}}
{{EngvarB|date=January 2019}}
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| caption = Penicillin core structure, where "R" is the variable group
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| Drugs.com = {{drugs.com|CONS|penicillin-oral-injection-intravenous-intramuscular.html}}
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| pregnancy_US = B
| pregnancy_US_comment = <ref>{{cite journal | url=http://www.aafp.org/afp/2006/0915/p1035.html | title=Tips from Other Journals – Antibiotic Use During Pregnancy and Lactation | issue=6 | page=1035 | date=September 15, 2006 | access-date=September 25, 2015 | vauthors=Walling AD | journal=American Family Physician | volume=74 | archive-date=December 15, 2016 | archive-url=https://web.archive.org/web/20161215140503/http://www.aafp.org/afp/2006/0915/p1035.html | url-status=live }}</ref>
| legal_status = Rx-only
| routes_of_administration = [[Intravenous]], [[intramuscular]], [[oral administration|by mouth]]
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| metabolism = Liver
| elimination_half-life = Between 0.5 and 56 hours
| excretion = Kidneys
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<!-- Definition and medical uses -->
'''Penicillins''' ('''P''', '''PCN''' or '''PEN''') are a group of [[beta-lactam antibiotic|β-lactam antibiotics]] originally obtained from ''[[Penicillium]]'' [[Mold (fungus)|mould]]s, principally ''[[Penicillium chrysogenum|P. chrysogenum]]'' and ''[[Penicillium rubens|P. rubens]]''. Most penicillins in clinical use are synthesised by ''[[Penicillium chrysogenum|P. chrysogenum]]'' using [[industrial fermentation|deep tank fermentation]]<ref>{{cite web|url=https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html|title=American Chemical Society National Historic Chemical Landmarks. Penicillin Production through Deep-tank Fermentation|website=American Chemical Society|date=2008-06-12|access-date=2022-06-15|archive-date=2020-10-24|archive-url=https://web.archive.org/web/20201024034317/https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html|url-status=live}}</ref> and then purified.<ref>{{cite journal | vauthors = Barreiro C, García-Estrada C | title = Proteomics and Penicillium chrysogenum: Unveiling the secrets behind penicillin production | journal = Journal of Proteomics | volume = 198 | pages = 119–31 | date = April 2019 | pmid = 30414515 | doi = 10.1016/j.jprot.2018.11.006 | publisher = Elsevier | s2cid = 53250114 }}</ref><ref>{{cite web |vauthors=Meštrović T |title=Penicillin Production |url=https://www.news-medical.net/health/Penicillin-Production.aspx |website=News Medical Life Sciences |date=2018-08-29 |access-date=2022-06-15 |archive-date=2023-04-04 |archive-url=https://web.archive.org/web/20230404010053/https://www.news-medical.net/health/Penicillin-Production.aspx |url-status=live }}</ref> A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: [[benzylpenicillin|penicillin G]] ([[intramuscular injection|intramuscular]] or [[Intravenous therapy|intravenous use]]) and [[phenoxymethylpenicillin|penicillin V]] (given by mouth). Penicillins were among the first medications to be effective against many [[bacterial infection]]s caused by [[staphylococcus|staphylococci]] and [[streptococcus|streptococci]]. They are still widely used today for various bacterial infections, though many types of [[bacteria]] have developed [[antibiotic resistance|resistance]] following extensive use.

<!-- Side effects and mechanism -->
In the United States, 10% of the population claims [[Side effects of penicillin#Allergies and cross sensitivities|penicillin allergies]], but because the frequency of positive skin test results decreases by 10% with each year of avoidance, 90% of these patients can eventually tolerate penicillin. Additionally, those with penicillin allergies can usually tolerate [[cephalosporin]]s (another group of β-lactam) because the [[Immunoglobulin E|immunoglobulin E (IgE)]] cross-reactivity is only 3%.<ref>{{cite journal | vauthors = Wanat M, Anthierens S, Butler CC, Savic L, Savic S, Pavitt SH, Sandoe JA, Tonkin-Crine S | title = Management of penicillin allergy in primary care: a qualitative study with patients and primary care physicians | journal = BMC Family Practice | volume = 22 | issue = 1 | article-number = 112 | date = June 2021 | pmid = 34116641 | pmc = 8194168 | doi = 10.1186/s12875-021-01465-1 | doi-access = free }}</ref>

<!-- History and culture -->
Penicillin was discovered in 1928 by the Scottish physician [[Alexander Fleming]] as a crude extract of ''P. rubens''.<ref name=":02">{{cite journal|vauthors=Lalchhandama K|date=2020|title=Reappraising Fleming's snot and mould|journal=Science Vision|volume=20|issue=1|pages=29–42|doi=10.33493/scivis.20.01.03|doi-access=free}}</ref> Fleming's student Cecil George Paine was the first to successfully use penicillin to treat eye infection ([[neonatal conjunctivitis]]) in 1930. The purified compound (penicillin F) was isolated in 1940 by a research team led by [[Howard Florey]] and [[Ernst Boris Chain]] at the [[University of Oxford]]. Fleming first used the purified penicillin to treat streptococcal [[meningitis]] in 1942.<ref name="Fleming 1943 434–438">{{Cite journal| vauthors = Fleming A |date=1943|title=Streptococcal Meningitis treated With Penicillin. |journal=The Lancet|language=en|volume=242|issue=6267|pages=434–38|doi=10.1016/S0140-6736(00)87452-8}}</ref> The 1945 [[Nobel Prize in Physiology or Medicine]] was shared by Chain, Fleming and Florey.

Several semisynthetic penicillins are effective against a broader spectrum of bacteria: these include the [[antistaphylococcal penicillins]], [[aminopenicillin]]s, and [[antipseudomonal penicillins]].

== Nomenclature ==
The term "penicillin" is defined as the natural product of ''[[Penicillium]]'' mould with antimicrobial activity.<ref name="Robinson1947">{{cite journal | vauthors = Robinson FA | title = Chemistry of penicillin | journal = The Analyst | volume = 72 | issue = 856 | pages = 274–76 | date = July 1947 | pmid = 20259048 | doi = 10.1039/an9477200274 | bibcode = 1947Ana....72..274R }}</ref> It was coined by [[Alexander Fleming]] on 7 March 1929 when he discovered the antibacterial property of ''[[Penicillium rubens]]''.<ref name=":5">{{cite journal | vauthors = Diggins FW | title = The true history of the discovery of penicillin, with refutation of the misinformation in the literature | journal = British Journal of Biomedical Science | volume = 56 | issue = 2 | pages = 83–93 | date = 1999 | pmid = 10695047 }}</ref> Fleming explained in his 1929 paper in the ''British Journal of Experimental Pathology'' that "to avoid the repetition of the rather cumbersome phrase 'Mould broth filtrate', the name 'penicillin' will be used."<ref name="pmid699420022">{{cite journal | vauthors = Krylov AK | title = [Gastroenterologic aspects of the clinical picture of internal diseases] | journal = Terapevticheskii Arkhiv | volume = 63 | issue = 2 | pages = 139–41 | year = 1929 | pmid = 2048009 | pmc = 2041430}}; Reprinted as {{cite journal|vauthors=Fleming A|year=1979|title=On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae|journal=British Journal of Experimental Pathology|volume=60|issue=1|pages=3–13|pmc=2041430|jstor=4452419}}</ref> The name thus refers to the scientific name of the mould, as described by Fleming in his Nobel lecture in 1945:

<blockquote>I have been frequently asked why I invented the name "Penicillin". I simply followed perfectly orthodox lines and coined a word which explained that the substance penicillin was derived from a plant of the genus Penicillium just as many years ago the word "[[Digitalin]]" was invented for a substance derived from the plant ''[[Digitalis]]''.<ref>{{cite web|date=1945|title=Nobel Lecture|url=https://www.nobelprize.org/prizes/medicine/1945/fleming/lecture/|access-date=19 July 2020|website=www.nobelprize.org|vauthors=Fleming A|archive-date=31 March 2018|archive-url=https://web.archive.org/web/20180331001640/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf|url-status=live}}</ref></blockquote>

In modern usage ''penicillin'' is used more broadly to refer to any [[beta-lactam|β-lactam]] antimicrobial that contains a [[thiazolidine]] ring fused to the β-lactam core and may or may not be a natural product.<ref>{{cite book | vauthors = Patrick GL | title=Medicinal Chemistry | edition=6th |date=2017 |page=425 |location=Oxford, UK |publisher=Oxford University Press |isbn=978-0-19-874969-1 }}</ref> Like most natural products, penicillin is present in ''Penicillium'' moulds as a mixture of active constituents ([[gentamicin]] is another example of a natural product that is an ill-defined mixture of active components).<ref name="Robinson1947" /> The principal active components of ''Penicillium'' are listed in the following table:''<ref name="ScienceNews1945">{{cite journal |author=<!--Staff writer(s); no by-line.--> |title=Recommendations of the International Conference on Penicillin. |journal=Science |date=1945-01-12 |volume=101 |issue=2611 |pages=42–43 |doi=10.1126/science.101.2611.42|pmid=17758593 |bibcode=1945Sci...101...42. }}</ref><ref name="Science1945">{{cite journal |author1=Committee on Medical Research |author2=The Medical Research Council |title=Chemistry of Penicillin |journal=Science |date=1945 |volume=102 |issue=2660 |pages=627–29 |doi=10.1126/science.102.2660.627 |publisher=American Association for the Advancement of Science |issn=0036-8075 |bibcode=1945Sci...102..627M |pmid=17788243 |jstor=1673446 }}</ref>

{| class="wikitable" width="auto" style="text-align: left"
! Chemical name
! UK nomenclature
! US nomenclature
! Potency relative <br /> to penicillin G<ref>{{cite journal | vauthors = Eagle H | title = The Relative Activity of Penicillins F, G, K, and X Against Spirochetes and Streptococci in Vitro | journal = Journal of Bacteriology | volume = 52 | issue = 1 | pages = 81–88 | date = July 1946 | pmid = 16561156 | pmc = 518141 | doi = 10.1128/JB.52.1.81-88.1946 }}</ref>
|-
| 2-Pentenylpenicillin || Penicillin I || Penicillin F<ref name="PenF">{{cite web
 |url=https://pubchem.ncbi.nlm.nih.gov/compound/6438232
 |title=Penicillin F
 |website=PubChem
 |publisher=National Center for Biotechnology Information, National Library of Medicine
 |access-date=2020-12-26
 |archive-date=2021-05-07
 |archive-url=https://web.archive.org/web/20210507122647/https://pubchem.ncbi.nlm.nih.gov/compound/6438232
 |url-status=live
 }}</ref> || 70–82%
|-
| [[Benzylpenicillin]] || Penicillin II || Penicillin G<ref name="PenG">{{cite web
 |url=https://pubchem.ncbi.nlm.nih.gov/compound/Penicillin-g
 |title=Penicillin G
 |website=PubChem
 |publisher=National Center for Biotechnology Information, National Library of Medicine
 |access-date=2020-12-26
 |archive-date=2020-12-25
 |archive-url=https://web.archive.org/web/20201225184249/https://pubchem.ncbi.nlm.nih.gov/compound/Penicillin-g
 |url-status=live
 }}</ref> || 100%
|-
| ''p''-Hydroxybenzylpenicillin || Penicillin III || Penicillin X<ref name="PenX">{{cite web
 |url=https://pubchem.ncbi.nlm.nih.gov/compound/120720
 |title=Penicillin X
 |website=PubChem
 |publisher=National Center for Biotechnology Information, National Library of Medicine
 |access-date=2020-12-26
 |archive-date=2021-05-05
 |archive-url=https://web.archive.org/web/20210505172810/https://pubchem.ncbi.nlm.nih.gov/compound/120720
 |url-status=live
 }}</ref> || 130–140%
|-
| ''n''-Heptylpenicillin || Penicillin IV || Penicillin K<ref name="PenK">{{cite web
 |url=https://pubchem.ncbi.nlm.nih.gov/compound/12314049
 |title=Penicillin K
 |website=PubChem
 |publisher=National Center for Biotechnology Information, National Library of Medicine
 |access-date=2020-12-26
 |archive-date=2021-05-06
 |archive-url=https://web.archive.org/web/20210506205742/https://pubchem.ncbi.nlm.nih.gov/compound/12314049
 |url-status=live
 }}</ref> || 110–120%
|}

Other minor active components of ''Penicillium'' include [[penicillin O]],<ref>{{cite web
 |url=https://pubchem.ncbi.nlm.nih.gov/compound/71365
 |title=Penicillin O
 |website=PubChem
 |publisher=National Center for Biotechnology Information, National Library of Medicine
 |access-date=2020-12-26
 |archive-date=2021-05-05
 |archive-url=https://web.archive.org/web/20210505172811/https://pubchem.ncbi.nlm.nih.gov/compound/71365
 |url-status=live
 }}</ref><ref>{{cite journal | vauthors = Fishman LS, Hewitt WL | title = The natural penicillins | journal = The Medical Clinics of North America | volume = 54 | issue = 5 | pages = 1081–99 | date = September 1970 | pmid = 4248661 | doi = 10.1016/S0025-7125(16)32579-2 }}</ref> penicillin U1, and penicillin U6. Other named constituents of natural ''Penicillium'', such as penicillin A, were subsequently found not to have antibiotic activity and are not chemically related to antibiotic penicillins.<ref name="Robinson1947"/>

The precise constitution of the penicillin extracted depends on the species of ''Penicillium'' mould used and on the nutrient media used to culture the mould.<ref name="Robinson1947"/> Fleming's original strain of ''Penicillium rubens'' produces principally penicillin F, named after Fleming. But penicillin F is unstable, difficult to isolate, and produced by the mould in small quantities.<ref name="Robinson1947"/>

The principal commercial strain of ''[[Penicillium chrysogenum]]'' (the Peoria strain) produces [[penicillin G]] as the principal component when corn steep liquor is used as the culture medium.<ref name="Robinson1947"/> When [[phenoxyethanol]] or phenoxyacetic acid are added to the culture medium, the mould produces [[penicillin V]] as the main penicillin instead.<ref name="Robinson1947"/>

[[6-aminopenicillanic acid|6-Aminopenicillanic acid]] (6-APA) is a compound derived from penicillin G. 6-APA contains the beta-lactam core of penicillin G, but with the side chains stripped off; 6-APA is a useful precursor for manufacturing other penicillins. There are many semi-synthetic penicillins derived from 6-APA and these are in three groups: antistaphylococcal penicillins, broad-spectrum penicillins, and antipseudomonal penicillins. The semi-synthetic penicillins are all referred to as penicillins because they are all derived ultimately from penicillin G.

=== Penicillin units ===
* One unit of penicillin G sodium is defined as 0.600 micrograms. Therefore, 2 million units (2 megaunits) of penicillin G is 1.2 g.<ref>{{cite web |title=Benzylpenicillin sodium 1200mg Powder for Injection |author=Genus Pharmaceuticals |website=Electronic medicines compendium |publisher=Datapharm Ltd. |date=2020-11-30 |url=https://www.medicines.org.uk/emc/product/7381/smpc |access-date=2020-12-28 |archive-date=2021-01-15 |archive-url=https://web.archive.org/web/20210115210213/https://www.medicines.org.uk/emc/product/7381/smpc |url-status=live }}</ref>
* One unit of penicillin V potassium is defined as 0.625 micrograms. Therefore 400,000 units of penicillin V is 250&nbsp;mg.<ref>{{cite web|author=Sandoz GmbH|title=Penicillin-VK|publisher=US FDA|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/064071s006lbl.pdf|access-date=2020-12-28|archive-date=2021-01-21|archive-url=https://web.archive.org/web/20210121031128/https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/064071s006lbl.pdf|url-status=live}}</ref>

The use of units to prescribe penicillin is largely obsolete outside of the US. Since the original penicillin was an ill-defined mixture of active compounds (an amorphous yellow powder), the potency of penicillin varied from batch to batch. It was therefore impractical to prescribe 1 g of penicillin because the activity of 1 g of penicillin from one batch would be different from the activity from another batch. To address this problem, after manufacture, each batch of penicillin was standardised against a known unit of penicillin: each glass vial was then filled with the number of units required. In the 1940s, a vial of 5,000 Oxford units was standard,<ref>{{cite web |title=Penicillin, 5,000 Oxford Units |website=National Museum of American History |location=Behring Center, Washington, D.C. |url=https://americanhistory.si.edu/collections/search/object/nmah_1383607 |access-date=2020-12-28 |archive-date=2021-05-06 |archive-url=https://web.archive.org/web/20210506205630/https://americanhistory.si.edu/collections/search/object/nmah_1383607 |url-status=live }}</ref> but the depending on the batch, could contain anything from 15&nbsp;mg to 20&nbsp;mg of penicillin. Later, a vial of 1,000,000 international units became standard, and this could contain 2.5 g to 3 g of natural penicillin (a mixture of penicillin I, II, III, and IV and natural impurities). With the advent of pure penicillin G preparations (a white crystalline powder), there is little reason to prescribe penicillin in units, although units are still used for [[benzathine benzylpenicillin]] in the United States.

The "unit" of penicillin has had three previous definitions, and each definition was chosen as being roughly equivalent to the previous one.
* '''Oxford or Florey unit (1941).''' This was originally defined as the minimum amount of penicillin dissolved in 50 ml of meat extract that would inhibit the growth of a standard strain of ''Staphylococcus aureus'' (the [[Staphylococcus aureus#Standard strains|Oxford Staphylococcus]]). The reference standard was a large batch of impure penicillin kept in [[Sir William Dunn School of Pathology|Oxford]].<ref>{{cite journal | vauthors = Robinson GL | title = Penicillin in general practice | journal = Postgraduate Medical Journal | volume = 23 | issue = 256 | pages = 86–92 | date = February 1947 | pmid = 20284177 | pmc = 2529492 | doi = 10.1136/pgmj.23.256.86 }}</ref> The assay was later modified by Florey's group to a more reproducible "cup assay": in this assay, a penicillin solution was defined to contain one unit/ml of penicillin when 339 microlitres of the solution placed in a "cup" on a plate of solid agar produced a 24 millimetre zone of inhibition of growth of Oxford Staphylococcus.<ref name="Greenwood_2008">{{cite book| vauthors = Greenwood D |title=Antimicrobial Drugs: A Chronicle of a Twentieth Century Medical Triumph |date=2008 |location=Oxford, UK| publisher=Oxford University Press |page=107 |isbn=978-0-19-953484-5 }}</ref>{{rp|107}}<ref>{{cite journal | journal = Lancet | volume = 238 | issue = 6155 | pages = 177–189 | year = 1941 | title = Further observations on penicillin. | vauthors = Abraham EP, Chain E, Fletcher CM, Gardner AD, Heatley NG, Jennings MA, Florey HW | doi = 10.1016/S0140-6736(00)72122-2 }}</ref><ref name="Foster1943">{{cite journal | vauthors = Foster JW, Woodruff HB | title = Microbiological Aspects of Penicillin: I. Methods of Assay | journal = Journal of Bacteriology | volume = 46 | issue = 2 | pages = 187–202 | date = August 1943 | pmid = 16560688 | pmc = 373803 | doi = 10.1128/JB.46.2.187-202.1943 }}</ref>
* '''First International Standard (1944).''' A single 8 gram batch of pure crystalline penicillin G sodium was stored at The [[National Institute for Medical Research]] in [[Mill Hill]], London (the International Standard). One penicillin unit was defined at 0.6 micrograms of the International Standard. An impure "working standard" was also defined and was available in much larger quantities distributed around the world: one unit of the working standard was 2.7 micrograms (the amount per unit was much larger because of the impurities). At the same time, the cup assay was refined, where instead of specifying a zone diameter of 24&nbsp;mm, the zone size were instead plotted against a reference curve to provide a readout on potency.<ref name="Foster1943"/><ref name="ScienceNews1945"/><ref name="Hartley1945">{{cite journal | vauthors = Hartley P | title = World Standard and Unit for Penicillin | journal = Science | volume = 101 | issue = 2634 | pages = 637–38 | date = June 1945 | pmid = 17844083 | doi = 10.1126/science.101.2634.637 | bibcode = 1945Sci...101..637H }}</ref>
* '''Second International Standard (1953).''' A single 30 gram batch of pure crystalline penicillin G sodium was obtained: this was also stored at Mill Hill. One penicillin unit was defined as 0.5988 micrograms of the Second International Standard.<ref>{{cite journal | vauthors = Humphrey JH, Musset MV, Perry WL | title = The second international standard for penicillin | journal = Bulletin of the World Health Organization | volume = 9 | issue = 1 | pages = 15–28 | year = 1953 | pmid = 13082387 | pmc = 2542105 }}</ref>

There is an older unit for penicillin V that is not equivalent to the current penicillin V unit. The reason is that the US FDA incorrectly assumed that the potency of penicillin V is the same mole-for-mole as penicillin G. In fact, penicillin V is less potent than penicillin G, and the current penicillin V unit reflects that fact.
* '''First international unit of penicillin V (1959).''' One unit of penicillin V was defined as 0.590 micrograms of a reference standard held at Mill Hill in London.<ref>{{cite journal | vauthors = Humphrey JH, Lightbown JW, Mussett MV | title = International Standard for phenoxymethylpenicillin | journal = Bulletin of the World Health Organization | volume = 20 | pages = 1221–27 | year = 1959 | issue = 6 | pmid = 14405369 | pmc = 2537888 }}</ref> This unit is now obsolete.

A similar standard was also established for penicillin K.<ref>{{cite journal | vauthors = Humphrey JH, Lightbown JW | title = The international reference preparation of penicillin K | journal = Bulletin of the World Health Organization | volume = 10 | issue = 6 | pages = 895–99 | year = 1954 | pmid = 13199652 | pmc = 2542178 }}</ref>

== Types ==
Penicillins consist of a distinct 4-membered [[beta-lactam]] ring, in addition to a thiazolide ring and an R side chain. The main distinguishing feature between variants within this family is the ''R substituent''. 

This side chain is connected to the 6-aminopenicillanic acid residue and results in ''variations'' in the antimicrobial spectrum, stability and susceptibility to [[beta-lactamase]]s of each type.
=== Natural penicillins ===
Penicillin G (benzylpenicillin) was first produced from a [[penicillium]] fungus that occurs in nature. The strain of fungus used today for the manufacture of penicillin G was created by [[genetic engineering]] to improve the yield in the manufacturing process. None of the other natural penicillins (F, K, N, X, O, U1 or U6) are currently in clinical use.

===Semi-synthetic penicillin===
{{missing information|section|why – need to take stuff from the PV article History section on how it magically makes more|date=December 2022}}
Penicillin V (phenoxymethylpenicillin) is produced by adding the [[Precursor (chemistry)|precursor]] phenoxyacetic acid to the medium in which a genetically modified strain{{dubious|reason=Discovered before GMO, in 1946–48. Maybe split into a follow up sentence that says GM is done to optimize production?|date=December 2022}} of the [[penicillium]] fungus is being cultured.

=== Antibiotics created from 6-APA ===
There are three major groups of other [[semisynthesis|semi-synthetic]] [[antibiotic]]s related to the penicillins. They are synthesised by adding various side-chains to the [[Precursor (chemistry)|precursor]] [[6-APA]], which is isolated from penicillin G. These are the antistaphylococcal antibiotics, broad-spectrum antibiotics and antipseudomonal antibiotics.

====Antistaphylococcal antibiotics====
* [[Cloxacillin]] (by mouth or by injection)
* [[Dicloxacillin]] (by mouth or by injection)
* [[Flucloxacillin]] (by mouth or by injection)
* [[Methicillin]] (injection only)
* [[Nafcillin]] (injection only)
* [[Oxacillin]] (by mouth or by injection)
Antistaphylococcal antibiotics are so-called because they are resistant to being broken down by staphylococcal [[Beta-lactamase|penicillinase]]. They are also, therefore, referred to as being penicillinase-resistant.

====Broad-spectrum antibiotics====
This group of antibiotics is called "broad-spectrum" because they are active against a wide range of Gram-negative bacteria such as ''[[Escherichia coli]]'' and ''[[Salmonella typhi]]'', for which penicillin is not suitable. However, resistance in these organisms is now common.
* [[Ampicillin]]
* [[Amoxicillin]]

There are many ampicillin precursors in existence. These are inactive compounds that are broken down in the gut to release ampicillin. None of these pro-drugs of ampicillin is in current use:
* [[Pivampicillin]] (pivaloyloxymethyl ester of ampicillin)
* [[Bacampicillin]]
* [[Metampicillin]] (formaldehyde ester of ampicillin)
* [[Talampicillin]]
* [[Hetacillin]] (ampicillin conjugated to acetone)

[[Epicillin]] is an aminopenicillin that has never seen widespread clinical use.

====Antipseudomonal antibiotics====
The Gram-negative species, ''[[Pseudomonas aeruginosa]],'' is naturally resistant to many antibiotic classes. There were many efforts in the 1960s and 1970s to develop antibiotics that are active against ''Pseudomonas'' species. There are two chemical classes within the group: carboxypenicillins and ureidopenicillins. All are given by injection: none can be given by mouth.

===== Carboxypenicillins =====
* [[Carbenicillin]]
* [[Ticarcillin]]
* [[Temocillin]]

===== Ureidopenicillins =====
* [[Mezlocillin]]
* [[Piperacillin]]
* [[Azlocillin]]

=== β-lactamase inhibitors ===
* [[Clavulanic acid]]
* [[Sulbactam]]
* [[Tazobactam]]

==Medical usage==
The term "penicillin", when used by itself, may refer to either of two [[chemical compound]]s, penicillin G or penicillin V.
{| class="wikitable"
|-
! Common name !!Chemical name|| Method of<br />administration
|-
|[[Penicillin V]]|| phenoxymethylpenicillin || [[Oral administration|oral]]
|-
|[[Penicillin G]]|| benzylpenicillin || [[intravenous]] <br /> [[intramuscular]]
|}

=== Penicillin G ===
Penicillin G is destroyed by stomach acid, so it cannot be taken by mouth, but doses as high as 2.4 g can be given (much higher than penicillin V). It is given by intravenous or intramuscular injection. It can be formulated as an insoluble salt, and there are two such formulations in current use: [[procaine penicillin]] and [[benzathine benzylpenicillin]]. When a high concentration in the blood must be maintained, penicillin G must be administered at relatively frequent intervals, because it is eliminated quite rapidly from the bloodstream by the kidney.

Penicillin G is licensed for use to treat [[septicaemia]], [[empyema]], [[pneumonia]], [[pericarditis]], [[endocarditis]] and [[meningitis]] caused by susceptible strains of staphylococci and streptococci. It is also licensed for the treatment of [[anthrax]], [[actinomycosis]], cervicofacial disease, thoracic and abdominal disease, [[Clostridium|clostridial infections]], [[botulism]], [[gas gangrene]] (with accompanying debridement and/or surgery as indicated), [[tetanus]] (as an adjunctive therapy to human tetanus immune globulin), [[diphtheria]] (as an adjunctive therapy to antitoxin and for the prevention of the carrier state), [[erysipelothrix]] endocarditis, [[acute necrotizing ulcerative gingivitis|fusospirochetosis]] (severe infections of the oropharynx, lower respiratory tract and genital area), ''[[Listeria]]'' infections, meningitis, endocarditis, ''[[Pasteurella]]'' infections including bacteraemia and meningitis, [[Haverhill fever]]; [[rat-bite fever]] and [[Neisseria gonorrhoeae|disseminated gonococcal infections]], [[Neisseria meningitidis|meningococcal]] meningitis and/or septicaemia caused by penicillin-susceptible organisms and syphilis.<ref name="FDA2016">{{cite web |title=Penicillin G Potassium Injection, USP |publisher=US FDA |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050638s019lbl.pdf |date=July 2016 |access-date=2020-12-28 |archive-date=2021-04-01 |archive-url=https://web.archive.org/web/20210401085740/https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050638s019lbl.pdf |url-status=live }}</ref>

=== Penicillin V ===
Penicillin V can be taken by mouth because it is relatively resistant to stomach acid. Doses higher than 500&nbsp;mg are not fully effective because of poor absorption. It is used for the same bacterial infections as those of penicillin G and is the most widely used form of penicillin.<ref>{{Citation|vauthors=Pandey N, Cascella M|title=Beta Lactam Antibiotics|date=2020|url=https://www.ncbi.nlm.nih.gov/books/NBK545311/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=31424895|access-date=2021-01-05|archive-date=2020-12-15|archive-url=https://web.archive.org/web/20201215050755/https://www.ncbi.nlm.nih.gov/books/NBK545311/|url-status=live}}</ref> However, it is not used for diseases, such as [[endocarditis]], where high blood levels of penicillin are required.

===Bacterial susceptibility===

Because penicillin resistance is now so common, other antibiotics are now the preferred choice for treatments. For example, penicillin used to be the first-line treatment for infections with ''[[Neisseria gonorrhoeae]]'' and ''[[Neisseria meningitidis]]'', but it is no longer recommended for treatment of these infections. Penicillin resistance is now very common in ''[[Staphylococcus aureus]]'', which means penicillin should not be used to treat infections caused by ''S. aureus'' infection unless the infecting strain is known to be susceptible.

{| class="wikitable"
|-
! '''Bacterium''' !! '''Susceptible (S)''' !! '''Intermediate (I)''' || '''Resistant (R)'''
|-
| ''[[Staphylococcus aureus]]'' || ≤0.12 mcg/ml || - || ≥0.25 mcg/ml
|-
| ''[[Streptococcus pneumoniae]]'' [[meningitis]] || ≤0.06 mcg/ml || - || ≥0.12 mcg/ml
|-
| ''Streptococcus pneumoniae'' (not meningitis) || ≤2 mcg/ml || || ≥8 mcg/ml
|-
| [[Streptococcus viridans|''Streptococcus'' Viridans group]] || 0.12 mcg/ml || 0.25–2 mcg/ml || 4 mcg/ml
|-
| ''[[Listeria monocytogenes]]'' || ≤2 mcg/ml || - || -
|-
| ''[[Bacillus anthracis]]'' || ≤0.12 mcg/ml || - || ≥0.25 mcg/ml
|}

== Side effects ==
{{Main|Side effects of penicillin}}
Common (≥ 1% of people) [[adverse drug reaction]]s associated with use of the penicillins include [[diarrhoea]], [[hypersensitivity]], [[nausea]], [[rash]], [[neurotoxicity]], [[urticaria]], and [[superinfection]] (including [[candidiasis]]). Infrequent adverse effects (0.1–1% of people) include [[fever]], [[vomiting]], [[erythema]], [[dermatitis]], [[angioedema]], [[seizures]] (especially in people with [[epilepsy]]), and [[pseudomembranous colitis]].<ref name="AMH2006">{{cite book|title=Australian Medicines Handbook|title-link=Australian Medicines Handbook|publisher=Australian Medicines Handbook|year=2006|isbn=978-0-9757919-2-9|veditors=Rossi S|location=Adelaide}}</ref> Penicillin can also induce [[serum sickness]] or a [[serum sickness-like reaction]] in some individuals. Serum sickness is a [[type III hypersensitivity]] reaction that occurs one to three weeks after exposure to drugs including penicillin. It is not a true drug allergy, because allergies are [[type I hypersensitivity]] reactions, but repeated exposure to the offending agent can result in an anaphylactic reaction.<ref>{{cite journal | vauthors = Bhattacharya S | title = The facts about penicillin allergy: a review | journal = Journal of Advanced Pharmaceutical Technology & Research | volume = 1 | issue = 1 | pages = 11–17 | date = January 2010 | doi = 10.4103/2231-4040.70513 | doi-access = free | pmid = 22247826 | pmc = 3255391 }}</ref><ref>{{cite journal | vauthors = Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ | title = Antibiotic allergy | journal = Lancet | volume = 393 | issue = 10167 | pages = 183–98 | date = January 2019 | pmid = 30558872 | pmc = 6563335 | doi = 10.1016/S0140-6736(18)32218-9 }}</ref> Allergy will occur in 1–10% of people, presenting as a skin rash after exposure. IgE-mediated [[anaphylaxis]] will occur in approximately 0.01% of patients.<ref name=":1">{{cite book| vauthors = Hitchings A, Lonsdale D, Burrage D, Baker E | title = Top 100 drugs: clinical pharmacology and practical prescribing |date=2015 |isbn=978-0-7020-5516-4 |pages=174–81 | publisher = Churchill Livingstone }}</ref><ref name="AMH2006" />

Pain and inflammation at the injection site are also common for [[Parenteral#Parenteral by injection or infusion|parenterally]] administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin. The condition is known as [[livedoid dermatitis]] or Nicolau syndrome.<ref>{{cite journal| vauthors = Kim KK, Chae DS |date=2015|title=Nicolau syndrome: A literature review |journal=World Journal of Dermatology |volume=4 |issue=2 |page=103 |doi=10.5314/wjd.v4.i2.103|doi-access=free }}</ref><ref>{{cite journal | vauthors = Saputo V, Bruni G | title = [Nicolau syndrome caused by penicillin preparations: review of the literature in search for potential risk factors] | journal = La Pediatria Medica e Chirurgica | volume = 20 | issue = 2 | pages = 105–23 | date = 1998 | pmid = 9706633 }}</ref>

== Structure ==
[[File:Penicillin-G 3D.png|thumb|right|Chemical structure of Penicillin G. The sulfur and nitrogen of the five-membered [[thiazolidine]] ring are shown in yellow and blue respectively. The image shows that the thiazolidine ring and fused four-membered ''β''-lactam are not in the same [[Plane (geometry)|plane]].]]

The term "[[penam]]" is used to describe the common core skeleton of a member of the penicillins. This core has the molecular formula R-C<sub>9</sub>H<sub>11</sub>N<sub>2</sub>O<sub>4</sub>S, where R is the variable side chain that differentiates the penicillins from one another. The penam core has a [[molar mass]] of 243 g/mol, with larger penicillins having molar mass near 450—for example, cloxacillin has a molar mass of 436 g/mol. 6-APA (C<sub>8</sub>H<sub>12</sub>N<sub>2</sub>O<sub>3</sub>S) forms the basic structure of penicillins. It is made up of an enclosed dipeptide formed by the condensation of {{nowrap|<small>L</small>-cysteine}} and {{nowrap|<small>D</small>-valine}}. This results in the formations of β-lactam and thiazolidinic rings.<ref name=":6">{{Cite journal| vauthors = Fernandes R, Amador P, Prudêncio C |date=2013|title=β-Lactams: chemical structure, mode of action and mechanisms of resistance|journal=Reviews in Medical Microbiology|language=en|volume=24|issue=1|pages=7–17|doi=10.1097/MRM.0b013e3283587727|hdl=10400.22/7041|doi-access=free|hdl-access=free}}</ref>

The key structural feature of the penicillins is the four-membered β-lactam ring; this structural [[moiety (chemistry)|moiety]] is essential for penicillin's antibacterial activity. The β-lactam ring is itself fused to a five-membered [[thiazolidine]] ring. The fusion of these two rings causes the β-lactam ring to be more reactive than monocyclic β-lactams because the two fused rings distort the β-lactam [[amide bond]] and therefore remove the [[Resonance (chemistry)|resonance stabilisation]] normally found in these chemical bonds.<ref>Nicolaou (1996), p. 43.</ref> An acyl side side chain attached to the β-lactam ring.<ref>{{cite journal | vauthors = Fisher JF, Mobashery S | title = Three decades of the class A beta-lactamase acyl-enzyme | journal = Current Protein & Peptide Science | volume = 10 | issue = 5 | pages = 401–07 | date = October 2009 | pmid = 19538154 | pmc = 6902449 | doi = 10.2174/138920309789351967 }}</ref>

A variety of β-lactam antibiotics have been produced following chemical modification from the 6-APA structure during synthesis, specifically by making chemical substitutions in the acyl side chain. For example, the first chemically altered penicillin, methicillin, had substitutions by methoxy groups at positions 2' and 6' of the 6-APA benzene ring from penicillin G.<ref name=":6" /> This difference makes methicillin resistant to the activity of [[Beta-lactamase|β-lactamase]], an enzyme by which many bacteria are naturally unsusceptible to penicillins.<ref name=":9">{{cite journal | vauthors = Morell EA, Balkin DM | title = Methicillin-resistant Staphylococcus aureus: a pervasive pathogen highlights the need for new antimicrobial development | journal = The Yale Journal of Biology and Medicine | volume = 83 | issue = 4 | pages = 223–33 | date = December 2010 | pmid = 21165342 | pmc = 3002151 }}</ref>

== Pharmacology ==

=== Entry into bacteria ===
Penicillin can easily enter bacterial cells in the case of [[Gram-positive bacteria|Gram-positive species]]. This is because Gram-positive bacteria do not have an outer cell membrane and are simply enclosed in a thick [[cell wall]].<ref>{{cite journal | vauthors = Silhavy TJ, Kahne D, Walker S | title = The bacterial cell envelope | journal = Cold Spring Harbor Perspectives in Biology | volume = 2 | issue = 5 | article-number = a000414 | date = May 2010 | pmid = 20452953 | pmc = 2857177 | doi = 10.1101/cshperspect.a000414 }}</ref> Penicillin molecules are small enough to pass through the spaces of [[glycoproteins]] in the cell wall. For this reason Gram-positive bacteria are very susceptible to penicillin (as first evidenced by the discovery of penicillin in 1928<ref name="Fleming1929" />{{Page needed|date=October 2025}}{{Clarify|reason=How was this "evidenced by the discovery"? Was it part of Fleming's initial results, or is it somehow relevant that the discovery was made in 1928? Should "by the" read "during the"?|date=October 2025}}{{Synthesis inline|date=October 2025|reason=I can't find a usage of the phrase "Gram-positive" in the paper.}}).<ref name=":8">{{cite journal | vauthors = Lambert PA | title = Cellular impermeability and uptake of biocides and antibiotics in Gram-positive bacteria and mycobacteria | journal = Journal of Applied Microbiology | volume = 92 | issue = Suppl | pages = 46S–54S | date = 2002 | pmid = 12000612 | doi = 10.1046/j.1365-2672.92.5s1.7.x | s2cid = 24067247 | doi-access =  }}</ref>

Penicillin, or any other molecule, enters [[Gram-negative bacteria]] in a different manner. The bacteria have thinner cell walls but the external surface is coated with an additional cell membrane, called the outer membrane. The outer membrane is a lipid layer ([[lipopolysaccharide]] chain) that blocks passage of water-soluble ([[hydrophilic]]) molecules like penicillin. It thus acts as the first line of defence against any toxic substance, which is the reason for relative resistance to antibiotics compared to Gram-positive species.<ref>{{cite journal | vauthors = Vergalli J, Bodrenko IV, Masi M, Moynié L, Acosta-Gutiérrez S, Naismith JH, Davin-Regli A, Ceccarelli M, van den Berg B, Winterhalter M, Pagès JM | title = Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria | journal = Nature Reviews. Microbiology | volume = 18 | issue = 3 | pages = 164–76 | date = March 2020 | pmid = 31792365 | doi = 10.1038/s41579-019-0294-2 | s2cid = 208520700 | url = https://discovery.ucl.ac.uk/id/eprint/10092508/3/Acosta%20Gutierrez_Porins%20and%20small-molecule%20translocation%20across%20the%20outer%20membrane%20of%20Gram-negative%20bacteria_AAM.pdf | access-date = 2021-07-30 | archive-date = 2021-10-22 | archive-url = https://web.archive.org/web/20211022163704/https://discovery.ucl.ac.uk/id/eprint/10092508/3/Acosta%20Gutierrez_Porins%20and%20small-molecule%20translocation%20across%20the%20outer%20membrane%20of%20Gram-negative%20bacteria_AAM.pdf | url-status = live }}</ref> But penicillin can still enter Gram-negative species by diffusing through aqueous channels called [[Porin (protein)|porins]] (outer membrane proteins), which are dispersed among the fatty molecules and can transport nutrients and antibiotics into the bacteria.<ref>{{cite book | vauthors = Masi M, Winterhalter M, Pagès JM | title = Bacterial Cell Walls and Membranes | chapter = Outer Membrane Porins | series = Subcellular Biochemistry | volume = 92 | pages = 79–123 | date = 2019 | pmid = 31214985 | doi = 10.1007/978-3-030-18768-2_4 | isbn = 978-3-030-18767-5 | s2cid = 195066847 }}</ref> Porins are large enough to allow diffusion of most penicillins, but the rate of diffusion through them is determined by the specific size of the drug molecules. For instance, penicillin G is large and enters through porins slowly; while smaller ampicillin and amoxicillin diffuse much faster.<ref name=":7">{{cite journal | vauthors = Soares GM, Figueiredo LC, Faveri M, Cortelli SC, Duarte PM, Feres M | title = Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs | journal = Journal of Applied Oral Science | volume = 20 | issue = 3 | pages = 295–309 | date = 2012 | pmid = 22858695 | pmc = 3881775 | doi = 10.1590/s1678-77572012000300002 }}</ref> In contrast, large vancomycin can not pass through porins and is thus ineffective for Gram-negative bacteria.<ref>{{cite journal | vauthors = Antonoplis A, Zang X, Wegner T, Wender PA, Cegelski L | title = Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant ''E. coli'' and Targets Cell-Wall Synthesis | journal = ACS Chemical Biology | volume = 14 | issue = 9 | pages = 2065–70 | date = September 2019 | pmid = 31479234 | pmc = 6793997 | doi = 10.1021/acschembio.9b00565 }}</ref> The size and number of porins are different in different bacteria. As a result of the two factors—size of penicillin and porin—Gram-negative bacteria can be unsusceptible or have varying degree of susceptibility to specific penicillin.<ref name=":11">{{cite journal | vauthors = Breijyeh Z, Jubeh B, Karaman R | title = Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It | journal = Molecules | volume = 25 | issue = 6 | page = 1340 | date = March 2020 | pmid = 32187986 | pmc = 7144564 | doi = 10.3390/molecules25061340 | doi-access = free }}</ref>

=== Mechanism of action ===
{{Main|Beta-lactam antibiotic}}
[[File:Penicillin spheroplast generation horizontal.svg|thumb|upright=2|Gram-negative bacteria that attempt to grow and divide in the presence of penicillin fail to do so, and instead end up shedding their cell walls.<ref name=":4" />]]
[[File:Penicillin inhibition.svg|thumb|upright=1.3|Penicillin and other β-lactam antibiotics act by inhibiting [[penicillin-binding proteins]], which normally catalyse cross-linking of bacterial cell walls.]]

Penicillin kills bacteria by inhibiting the completion of the synthesis of [[peptidoglycan]]s, the structural component of the [[bacterial cell wall]]. It specifically inhibits the activity of enzymes that are needed for the cross-linking of peptidoglycans during the final step in cell wall biosynthesis. It does this by binding to [[penicillin binding proteins]] with the β-lactam ring, a structure found on penicillin molecules.<ref>{{cite journal | vauthors = Yocum RR, Rasmussen JR, Strominger JL | title = The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase | journal = The Journal of Biological Chemistry | volume = 255 | issue = 9 | pages = 3977–86 | date = May 1980 | pmid = 7372662 | doi = 10.1016/S0021-9258(19)85621-1 | doi-access = free }}</ref><ref>{{cite web|title=Benzylpenicillin|url=https://www.drugbank.ca/drugs/DB01053|access-date=22 January 2019|website=www.drugbank.ca|archive-date=23 January 2019|archive-url=https://web.archive.org/web/20190123071652/https://www.drugbank.ca/drugs/DB01053|url-status=live}}</ref> This causes the cell wall to weaken due to fewer cross-links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell [[lysis]] and death.

Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. During the last stages of peptidoglycan biosynthesis, uridine diphosphate-''N''-acetylmuramic acid pentapeptide (UDP-MurNAc) is formed in which the fourth and fifth amino acids are both <small>D</small>-alanyl-<small>D</small>-alanine. The transfer of <small>D</small>-alanine is done (catalysed) by the [[enzyme]] [[DD-Transpeptidase|<small>DD</small>-transpeptidase]] ([[penicillin binding proteins|penicillin-binding proteins]] are such type).<ref name=":7"/> The structural integrity of bacterial cell wall depends on the [[Cross-link|cross linking]] of UDP-MurNAc and ''N''-acetyl glucosamine.<ref>{{cite journal | vauthors = DeMeester KE, Liang H, Jensen MR, Jones ZS, D'Ambrosio EA, Scinto SL, Zhou J, Grimes CL | title = Synthesis of Functionalized N-Acetyl Muramic Acids To Probe Bacterial Cell Wall Recycling and Biosynthesis | journal = Journal of the American Chemical Society | volume = 140 | issue = 30 | pages = 9458–65 | date = August 2018 | pmid = 29986130 | pmc = 6112571 | doi = 10.1021/jacs.8b03304 | bibcode = 2018JAChS.140.9458D }}</ref> Penicillin and other β-lactam antibiotics act as an analogue of <small>D</small>-alanine-<small>D</small>-alanine (the dipeptide) in UDP-MurNAc owing to conformational similarities. The <small>DD</small>-transpeptidase then binds the four-membered β-lactam [[cycloalkane|ring]] of penicillin instead of UDP-MurNAc.<ref name=":7" /> As a consequence, <small>DD</small>-transpeptidase is inactivated, the formation of cross-links between UDP-MurNAc and ''N''-acetyl glucosamine is blocked so that an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.<ref name=":3">{{cite journal | vauthors = Gordon E, Mouz N, Duée E, Dideberg O | title = The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance | journal = Journal of Molecular Biology | volume = 299 | issue = 2 | pages = 477–85 | date = June 2000 | pmid = 10860753 | doi = 10.1006/jmbi.2000.3740 }}</ref>

The enzymes that [[hydrolyze|hydrolyse]] the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death ([[cytolysis]]). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell wall's peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the [[glycopeptide antibiotics]] [[vancomycin]] and [[teicoplanin]], which are both much larger than the penicillins.<ref>{{cite book|vauthors=Van Bambeke F, Lambert D, Mingeot-Leclercq MP, Tulkens P|title=Mechanism of Action|date=1999|url=http://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-1999-3.pdf|access-date=2014-03-13|archive-date=2022-01-25|archive-url=https://web.archive.org/web/20220125025037/https://www.facm.ucl.ac.be/Full-texts-FACM/Vanbambeke-1999-3.pdf|url-status=live}}</ref>

Gram-positive bacteria are called [[protoplast]]s when they lose their cell walls. [[Gram-negative]] bacteria do not lose their cell walls completely and are called [[spheroplast]]s after treatment with penicillin.<ref name=":4">{{cite journal | vauthors = Cushnie TP, O'Driscoll NH, Lamb AJ | title = Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action | journal = Cellular and Molecular Life Sciences | volume = 73 | issue = 23 | pages = 4471–92 | date = December 2016 | pmid = 27392605 | doi = 10.1007/s00018-016-2302-2 | pmc = 11108400 | hdl = 10059/2129 | s2cid = 2065821 | url = https://zenodo.org/record/883501 | hdl-access = free | access-date = 2019-10-10 | archive-date = 2017-10-07 | archive-url = https://web.archive.org/web/20171007220157/https://zenodo.org/record/883501 | url-status = live }}</ref>

Penicillin shows a synergistic effect with [[aminoglycosides]], since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered [[Minimum Bactericidal Concentration|MBC]] for susceptible organisms.<ref>{{cite journal | vauthors = Winstanley TG, Hastings JG | title = Penicillin-aminoglycoside synergy and post-antibiotic effect for enterococci | journal = The Journal of Antimicrobial Chemotherapy | volume = 23 | issue = 2 | pages = 189–99 | date = February 1989 | pmid = 2708179 | doi = 10.1093/jac/23.2.189 }}</ref>

Penicillins, like other ''β''-lactam antibiotics, block not only the division of bacteria, including [[cyanobacteria]], but also the division of cyanelles, the [[Photosynthesis|photosynthetic]] [[organelle]]s of the [[glaucophyte]]s, and the division of [[chloroplast]]s of [[bryophyte]]s. In contrast, they have no effect on the [[plastid]]s of the highly developed [[vascular plant]]s. This supports the [[endosymbiotic theory]] of the [[evolution]] of plastid division in land plants.<ref>{{cite journal|vauthors=Kasten B, Reski R|author-link2=Ralf Reski|date=March 30, 1997|title=β-lactam antibiotics inhibit chloroplast division in a moss (Physcomitrella patens) but not in tomato (Lycopersicon esculentum)|journal=Journal of Plant Physiology|volume=150|pages=137–40|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=2640663|issue=1–2|doi=10.1016/S0176-1617(97)80193-9|bibcode=1997JPPhy.150..137K |access-date=March 30, 2009|archive-date=July 21, 2011|archive-url=https://web.archive.org/web/20110721001848/http://cat.inist.fr/?aModele=afficheN&cpsidt=2640663|url-access=subscription}}</ref>

Some bacteria produce enzymes that break down the β-lactam ring, called [[Beta-lactamase|β-lactamases]], which make the bacteria resistant to penicillin. Therefore, some penicillins are modified or given with other drugs for use against antibiotic-resistant bacteria or in immunocompromised patients. The use of clavulanic acid or tazobactam, β-lactamase inhibitors, alongside penicillin gives penicillin activity against β-lactamase-producing bacteria. β-Lactamase inhibitors irreversibly bind to β-lactamase preventing it from breaking down the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified penicillin that has activity against β-lactamase-producing bacteria due to an acyl side chain that protects the beta-lactam ring from β-lactamase.<ref name=":1" />

===Pharmacokinetics===
Penicillin has low protein binding in plasma. The [[bioavailability]] of penicillin depends on the type: penicillin G has low bioavailability, below 30%, whereas penicillin V has higher bioavailability, between 60 and 70%.<ref name="ncbi" />

Penicillin has a short half-life and is excreted via the kidneys.<ref name="ncbi">{{cite journal | vauthors = Levison ME, Levison JH | title = Pharmacokinetics and pharmacodynamics of antibacterial agents | journal = Infectious Disease Clinics of North America | volume = 23 | issue = 4 | pages = 791–815, vii | date = December 2009 | pmid = 19909885 | pmc = 3675903 | doi = 10.1016/j.idc.2009.06.008 }}</ref> This means it must be dosed at least four times a day to maintain adequate levels of penicillin in the blood. Early manuals on the use of penicillin, therefore, recommended injections of penicillin as frequently as every three hours, and dosing penicillin has been described as being similar to trying to fill a bath with the plug out.<ref name="Robinson1947"/> This is no longer required since much larger doses of penicillin are cheaply and easily available; however, some authorities recommend the use of continuous penicillin infusions for this reason.<ref>{{cite journal | vauthors = Walton AL, Howden BP, Grayson LM, Korman TM | title = Continuous-infusion penicillin home-based therapy for serious infections due to penicillin-susceptible pathogens | journal = International Journal of Antimicrobial Agents | volume = 29 | issue = 5 | pages = 544–48 | date = May 2007 | pmid = 17398076 | doi = 10.1016/j.ijantimicag.2006.10.018 }}</ref>

== Resistance ==
When Alexander Fleming discovered the crude penicillin in 1928, one important observation he made was that many bacteria were not affected by penicillin.<ref name="Fleming1929" /> This phenomenon was realised by [[Ernst Chain]] and [[Edward Abraham]] while trying to identify the exact of penicillin. In 1940 they discovered that unsusceptible bacteria like ''[[Escherichia coli]]'' produced specific enzymes that can break down penicillin molecules, thus making them resistant to the antibiotic. They named the enzyme [[penicillinase]].<ref name=":14">{{cite journal | vauthors = Abraham EP, Chain E | title = An enzyme from bacteria able to destroy penicillin. 1940 | journal = Reviews of Infectious Diseases | volume = 10 | issue = 4 | pages = 677–78 | date = 1940 | pmid = 3055168 | doi = 10.1038/146837a0 | s2cid = 4070796 | bibcode = 1940Natur.146..837A | doi-access = free }}</ref> Penicillinase is now classified as member of enzymes called β-lactamases. These β-lactamases are naturally present in many other bacteria, and many bacteria produce them upon constant exposure to antibiotics. In most bacteria, resistance can be through three different mechanisms&nbsp;– reduced permeability in bacteria, reduced binding affinity of the penicillin-binding proteins (PBPs) or destruction of the antibiotic through the expression of β-lactamase.<ref>{{cite journal | vauthors = Rice LB | title = Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones | journal = Mayo Clinic Proceedings | volume = 87 | issue = 2 | pages = 198–208 | date = February 2012 | pmid = 22305032 | pmc = 3498059 | doi = 10.1016/j.mayocp.2011.12.003 }}</ref> Using any of these, bacteria commonly develop resistance to different antibiotics, a phenomenon called [[multi-drug resistance]].

The actual process of resistance mechanism can be very complex. In case of reduced permeability in bacteria, the mechanisms are different between Gram-positive and Gram-negative bacteria. In Gram-positive bacteria, blockage of penicillin is due to changes in the cell wall. For example, resistance to vancomycin in ''S. aureus'' is due to additional peptidoglycan synthesis that makes the cell wall much thicker preventing effective penicillin entry.<ref name=":8" /> Resistance in Gram-negative bacteria is due to mutational variations in the structure and number of porins.<ref name=":11" /> In bacteria like ''Pseudomonas aeruginosa'', there is reduced number of porins; whereas in bacteria like ''Enterobacter'' species, ''Escherichia'' ''coli'' and ''Klebsiella pneumoniae'', there are modified porins such as non-specific porins (such as OmpC and OmpF groups) that cannot transport penicillin.<ref>{{cite journal |vauthors=Pagès JM, James CE, Winterhalter M |date=December 2008 |title=The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria |url=https://www.nature.com/articles/nrmicro1994 |url-status=live |journal=Nature Reviews. Microbiology |volume=6 |issue=12 |pages=893–903 |doi=10.1038/nrmicro1994 |pmid=18997824 |s2cid=6969441 |archive-url=https://web.archive.org/web/20130531000000/https://www.nature.com/articles/nrmicro1994 |archive-date=31 May 2013 |access-date=10 December 2024|url-access=subscription }} [https://salford-repository.worktribe.com/output/1430863/the-porin-and-the-permeating-antibiotic-a-selective-diffusion-barrier-in-gram-negative-bacteria Alt URL]</ref>

Resistance due to PBP alterations is highly varied. A common case is found in ''Streptococcus pneumoniae'' where there is mutation in the gene for PBP, and the mutant PBPs have decreased binding affinity for penicillins.<ref>{{cite journal | vauthors = Jacobs MR | title = Drug-resistant Streptococcus pneumoniae: rational antibiotic choices | journal = The American Journal of Medicine | volume = 106 | issue = 5A | pages = 19S–25S; discussion 48S–52S | date = May 1999 | pmid = 10348060 | doi = 10.1016/s0002-9343(98)00351-9 }}</ref> There are six mutant PBPs in ''S. pneumoniae'', of which PBP1a, PBP2b, PBP2x and sometimes PBP2a are responsible for reduced binding affinity.<ref name=":13" /> ''S. aureus'' can activate a hidden gene that produces a different PBP, PBD2, which has low binding affinity for penicillins.<ref>{{cite journal | vauthors = Peacock SJ, Paterson GK | title = Mechanisms of Methicillin Resistance in Staphylococcus aureus | journal = Annual Review of Biochemistry | volume = 84 | pages = 577–601 | date = 2015 | pmid = 26034890 | doi = 10.1146/annurev-biochem-060614-034516 | url = https://www.repository.cam.ac.uk/bitstream/1810/254765/1/HEFCE%20Exception%20sheet.pdf }}</ref> There is a different strain of ''S. aureus'' named [[Methicillin-resistant S. aureus|methicillin-resistant ''S. aureus'']] (MRSA) which is resistant not only to penicillin and other β-lactams, but also to most antibiotics. The bacterial strain developed after introduction of methicillin in 1959.<ref name=":9" /> In MRSA, mutations in the genes (''mec'' system) for PBP produce a variant protein called PBP2a (also termed PBP2'),<ref>{{cite journal | vauthors = Reygaert W | title = Methicillin-resistant Staphylococcus aureus (MRSA): molecular aspects of antimicrobial resistance and virulence | journal = Clinical Laboratory Science | volume = 22 | issue = 2 | pages = 115–19 | date = 2009 | pmid = 19534446 }}</ref> while making four normal PBPs. PBP2a has poor binding affinity for penicillin and also lacks glycosyltransferase activity required for complete peptidoglycan synthesis (which is carried out by the four normal PBPs).<ref name=":13">{{cite journal | vauthors = Zapun A, Contreras-Martel C, Vernet T | title = Penicillin-binding proteins and beta-lactam resistance | journal = FEMS Microbiology Reviews | volume = 32 | issue = 2 | pages = 361–85 | date = March 2008 | pmid = 18248419 | doi = 10.1111/j.1574-6976.2007.00095.x | doi-access = free }}</ref> In ''Helicobacter cinaedi'', there are multiple mutations in different genes that make PBP variants.<ref>{{cite journal | vauthors = Rimbara E, Mori S, Kim H, Suzuki M, Shibayama K | title = Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in β-Lactam Resistance in Helicobacter cinaedi | journal = Antimicrobial Agents and Chemotherapy | volume = 62 | issue = 2 | article-number = e02036-17 | date = February 2018 | pmid = 29203490 | pmc = 5786776 | doi = 10.1128/AAC.02036-17 }}</ref>

Enzymatic destruction by β-lactamases is the most important mechanism of penicillin resistance,<ref>{{cite journal | vauthors = Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VH, Takebayashi Y, Spencer J | title = β-Lactamases and β-Lactamase Inhibitors in the 21st Century | journal = Journal of Molecular Biology | volume = 431 | issue = 18 | pages = 3472–3500 | date = August 2019 | pmid = 30959050 | pmc = 6723624 | doi = 10.1016/j.jmb.2019.04.002 }}</ref> and is described as "the greatest threat to the usage [of penicillins]".<ref name=":15">{{cite journal | vauthors = Bonomo RA | title = β-Lactamases: A Focus on Current Challenges | journal = Cold Spring Harbor Perspectives in Medicine | volume = 7 | issue = 1 | article-number = a025239 | date = January 2017 | pmid = 27742735 | pmc = 5204326 | doi = 10.1101/cshperspect.a025239 }}</ref> It was the first discovered mechanism of penicillin resistance. During the experiments when purification and biological activity tests of penicillin were performed in 1940, it was found that ''E. coli'' was unsusceptible.<ref name="Davies">{{cite journal | vauthors = Davies J, Davies D | title = Origins and evolution of antibiotic resistance | journal = Microbiology and Molecular Biology Reviews | volume = 74 | issue = 3 | pages = 417–33 | date = September 2010 | pmid = 20805405 | pmc = 2937522 | doi = 10.1128/MMBR.00016-10 }}</ref> The reason was discovered as production of an enzyme penicillinase (hence, the first β-lactamase known) in ''E. coli'' that easily degraded penicillin.<ref name=":14" /> There are over 2,000 types of β-lactamases each of which has unique amino acid sequence, and thus, enzymatic activity.<ref name=":15" /> All of them are able to hydrolyse β-lactam rings but their exact target sites are different.<ref>{{cite journal | vauthors = Bush K | title = Past and Present Perspectives on β-Lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 62 | issue = 10 | article-number = e01076-18 | date = October 2018 | pmid = 30061284 | pmc = 6153792 | doi = 10.1128/AAC.01076-18 }}</ref> They are secreted on the bacterial surface in large quantities in Gram-positive bacteria but less so in Gram-negative species. Therefore, in a mixed bacterial infection, the Gram-positive bacteria can protect the otherwise penicillin-susceptible Gram-negative cells.<ref name=":7" />

There are unusual mechanisms in ''P. aeruginosa'', in which there can be biofilm-mediated resistance and formation of multidrug-tolerant [[persister cells]].<ref>{{cite journal | vauthors = Pang Z, Raudonis R, Glick BR, Lin TJ, Cheng Z | title = Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies | journal = Biotechnology Advances | volume = 37 | issue = 1 | pages = 177–92 | date = 2019 | pmid = 30500353 | doi = 10.1016/j.biotechadv.2018.11.013 | doi-access = free }}</ref>

== History ==
{{Main|History of penicillin}}

=== Discovery ===
{{main|Discovery of penicillin}}
[[File:Sample of penicillin mould presented by Alexander Fleming to Douglas Macleod, 1935 (9672239344).jpg|thumb|Sample of ''[[penicillium]]'' mould presented by [[Alexander Fleming]] to Douglas Macleod, 1935]]

Starting in the late-19th century there had been reports of the antibacterial properties of ''Penicillium'' mould, but scientists were unable to discern what process was causing the effect.<ref>{{cite book | vauthors = Dougherty TJ, Pucci MJ | title = Antibiotic Discovery and Development | publisher = Springer Science & Business Media | date = 2011 | pages = 79–80 }}</ref> The Scottish physician [[Alexander Fleming]] at [[St Mary's Hospital, London|St. Mary's Hospital]] in London (now part of [[Imperial College]]) was the first to show that ''[[Penicillium rubens]]'' had antibacterial properties.<ref>{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | title = Pharmaceutical Innovation: Revolutionizing Human Health | publisher = Chemical Heritage Foundation | date = 1999 | page = 162 }}</ref> On 3 September 1928 he observed by chance that fungal contamination of a bacterial culture (''[[Staphylococcus aureus]]'') appeared to kill the bacteria. He confirmed this observation with a new experiment on 28 September 1928.<ref>{{cite book | vauthors = Haven KF |title=Marvels of Science: 50 Fascinating 5-Minute Reads |publisher=Libraries Unlimited |location=Littleton, CO |year=1994 |page=182 |isbn=978-1-56308-159-0 }}</ref><ref>{{cite journal | vauthors = Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D | title = 10 x '20 Progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 56 | issue = 12 | pages = 1685–94 | date = June 2013 | pmc = 5403050 | doi = 10.3201/eid2305.161556 | pmid = 23599308 }}</ref> He published his experiment in 1929, and called the antibacterial substance (the fungal extract) penicillin.<ref name="Fleming1929">{{cite journal |title=On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ | vauthors = Fleming A | journal = British Journal of Experimental Pathology |year=1929 |volume=10|issue=3|pages=226–36|pmc=2048009}}
Reprinted as {{cite journal | vauthors = Fleming A | title = Classics in infectious diseases: on the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae by Alexander Fleming, Reprinted from the British Journal of Experimental Pathology 10:226–36, 1929 | journal = Reviews of Infectious Diseases | volume = 2 | issue = 1 | pages = 129–39 | year = 1980 | pmid = 6994200 | pmc = 2041430 | doi = 10.1093/clinids/2.1.129 }}</ref>

C. J. La Touche identified the fungus as ''Penicillium rubrum'' (later reclassified by [[Charles Thom]] as ''P. notatum'' and ''P. chrysogenum'', but later corrected as ''[[Penicillium rubens|P. rubens]]'').<ref>{{cite journal | vauthors = Houbraken J, Frisvad JC, Samson RA | title = Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens | journal = IMA Fungus | volume = 2 | issue = 1 | pages = 87–95 | date = June 2011 | pmid = 22679592 | pmc = 3317369 | doi = 10.5598/imafungus.2011.02.01.12 }}</ref> Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of ''Bacillus influenzae'' (now called ''[[Haemophilus influenzae]]'').<ref name="Lax2004">{{cite book| vauthors = Lax E  |url= https://archive.org/details/moldindrfloreysc00eric |title=The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle |publisher=Holt Paperbacks |year=2004 |isbn=978-0-8050-7778-0 }}</ref><ref name=Krylov1991>{{cite journal | vauthors = Krylov AK | title = [Gastroenterologic aspects of the clinical picture of internal diseases] | journal = Terapevticheskii Arkhiv | volume = 63 | issue = 2 | pages = 139–41 | year = 1991 | pmid = 2048009 }}</ref>
<!--Reprinted in {{cite journal | vauthors = Fleming A | title = On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929 | journal = Bulletin of the World Health Organization | volume = 79 | issue = 8 | pages = 780–90 | year = 2001 | pmid = 11545337 | pmc = 2566493 }}   This made absolutely no sense at all. The Russian paper is from 1991, and could not have been reprinted in Fleming's original 1929 paper. The ''Bulletin'' link is to an image PDF of of Fleming's paper. There is another link above to a reprint of Fleming's paper in ''Reviews of Infectious Diseases''-->

Fleming did not convince anyone that his discovery was important.<ref name=Lax2004 /> This was largely because penicillin was so difficult to isolate that its development as a drug seemed impossible. It is speculated that had Fleming been more successful at making other scientists interested in his work, penicillin would possibly have been developed years earlier.<ref name=Lax2004 />

The importance of his work has been recognised by the placement of an [[International Historic Chemical Landmark]] at the Alexander Fleming Laboratory Museum in London on 19 November 1999.<ref name="Landmark">{{cite web |title = Discovery and Development of Penicillin |url = https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html |publisher = American Chemical Society |work = International Historic Chemical Landmarks |access-date = August 21, 2018 |archive-date = June 28, 2019 |archive-url = https://web.archive.org/web/20190628035235/https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html |url-status = live }}</ref>

=== Development and medical application ===
[[File:Howard Walter Florey 1945.jpg|thumb|upright=0.8|[[Howard Florey]] (pictured), Alexander Fleming and [[Ernst Chain]] shared a [[Nobel Prize in Physiology or Medicine]] in 1945 for their work on penicillin.]]
In 1930 Cecil George Paine, a [[pathologist]] at the [[Sheffield Royal Infirmary|Royal Infirmary]] in [[Sheffield]], successfully treated [[Neonatal conjunctivitis|ophthalmia neonatorum]], a gonococcal infection in infants, with penicillin (fungal extract) on 25 November 1930.<ref name="Wainwright, M & Swan, HT 1986 42–56">{{cite journal | vauthors = Wainwright M, Swan HT | title = C.G. Paine and the earliest surviving clinical records of penicillin therapy | journal = Medical History | volume = 30 | issue = 1 | pages = 42–56 | date = January 1986 | pmid = 3511336 | pmc = 1139580 | doi = 10.1017/S0025727300045026 }}</ref><ref>{{cite journal | vauthors = Howie J | title = Penicillin: 1929-40 | journal = British Medical Journal | volume = 293 | issue = 6540 | pages = 158–59 | date = July 1986 | pmid = 3089435 | pmc = 1340901 | doi = 10.1136/bmj.293.6540.158 }}</ref><ref>{{cite journal | vauthors = Wainwright M | title = The history of the therapeutic use of crude penicillin | journal = Medical History | volume = 31 | issue = 1 | pages = 41–50 | date = January 1987 | pmid = 3543562 | pmc = 1139683 | doi = 10.1017/s0025727300046305 }}</ref>

In 1940 the Australian scientist [[Howard Florey]] (later Baron Florey) and a team of researchers ([[Ernst Boris Chain|Ernst Chain]], [[Edward Abraham]], [[Arthur Duncan Gardner]], [[Norman Heatley]], [[Margaret Jennings (scientist)|Margaret Jennings]], [[Jean Orr-Ewing]] and Arthur Gordon Sanders) at the [[Sir William Dunn School of Pathology]] of the [[University of Oxford]] made progress in making concentrated penicillin from fungal culture broth that showed both ''in vitro'' and ''[[in vivo]]'' bactericidal action.<ref name=":0" /><ref>{{Cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/chain-lecture.html|title=Ernst B. Chain – Nobel Lecture: The Chemical Structure of the Penicillins|website=www.nobelprize.org|access-date=2017-05-10|archive-date=2017-04-30|archive-url=https://web.archive.org/web/20170430172918/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/chain-lecture.html|url-status=live}}</ref> In 1941 they treated a policeman, [[Albert Alexander (police officer)|Albert Alexander]], with a severe face infection; his condition improved, but then supplies of penicillin ran out and he died. Subsequently, several other patients were treated successfully.<ref name="SW" /> In December 1942, survivors of the [[Cocoanut Grove fire]] in [[Boston]], United States, were the first burn patients to be successfully treated with penicillin.<ref>{{cite book | vauthors = Levy SB | title = The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers | publisher = Da Capo Press | year = 2002 | pages = 5–7 | isbn = 978-0-7382-0440-6 }}</ref>

The first successful use of pure penicillin was in 1942 when Fleming cured Harry Lambert of an infection of the nervous system (streptococcal [[meningitis]]) which would otherwise have been fatal. By that time the Oxford team could produce only a small amount. Florey willingly gave the only available sample to Fleming. Lambert showed improvement from the very next day of the treatment, and was completely cured within a week.<ref name=":42">{{cite journal | vauthors = Bennett JW, Chung KT | title = Alexander Fleming and the discovery of penicillin | journal = Advances in Applied Microbiology | volume = 49 | pages = 163–84 | date = 2001 | pmid = 11757350 | doi = 10.1016/s0065-2164(01)49013-7 | publisher = Elsevier | isbn = 978-0-12-002649-4 }}</ref><ref>{{Cite journal| vauthors = Cairns H, Lewin WS, Duthie ES, Smith H |date=1944|title=Pneumococcal Meningitis Treated with Penicillin |journal=The Lancet|language=en|volume=243|issue=6299|pages=655–59|doi=10.1016/S0140-6736(00)77085-1}}</ref> Fleming published his clinical trial in ''[[The Lancet]]'' in 1943.<ref name="Fleming 1943 434–438"/> Following the medical breakthrough, the British [[War Cabinet]] set up the Penicillin Committee on 5 April 1943 that led to projects for [[mass production]].<ref>{{Cite journal| vauthors = Mathews JA |date=2008|title=The Birth of the Biotechnology Era: Penicillin in Australia, 1943–80 |journal=Prometheus|volume=26|issue=4|pages=317–33|doi=10.1080/08109020802459306|s2cid=143123783|doi-access=free}}</ref><ref>{{Cite book|vauthors=Baldry P|url=https://books.google.com/books?id=rvs8AAAAIAAJ|title=The Battle Against Bacteria: A Fresh Look|date=1976|publisher=CUP Archive|isbn=978-0-521-21268-7|page=115|language=en|access-date=2020-12-31|archive-date=2021-05-05|archive-url=https://web.archive.org/web/20210505180529/https://books.google.com/books?id=rvs8AAAAIAAJ|url-status=live}}</ref>

=== Mass production ===
[[File:Penicillin Past, Present and Future- the Development and Production of Penicillin, England, 1943 D16965.jpg|thumb|A lab technician spraying penicillin mould into flasks of corn steep liquor, England, 1943]]
[[File:"Every Minute Lost on this Job may Mean.." - NARA - 514228 (edited).jpg|thumb|A World War II-era poster from a construction site for a penicillin factory. A military grave emphasizes the site's importance, as penicillin was urgently needed in wartime.]]
As the medical application was established, the Oxford team found that it was impossible to produce usable amounts in their laboratory.<ref name=SW /> Failing to persuade [[His Majesty's Government]], Florey and Heatley travelled to the US in June 1941 with their mould samples in order to interest the [[US federal government]] for large-scale production.<ref name=":10">{{cite journal |vauthors=Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D |date=June 2013 |title=10 x '20 Progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America |journal=Clinical Infectious Diseases |volume=56 |issue=12 |pages=1685–1694 |doi=10.1093/cid/cit152 |pmc=3707426 |pmid=23599308}}</ref><ref name=":2">{{Cite journal | vauthors = Braun A |date=December 2024 |title=A Most Miraculous Mold |journal=Smithsonian |volume=55 |issue=6 |page=32}}</ref> They approached the Northern Regional Research Laboratory (NRRL, now the [[National Center for Agricultural Utilization Research]]) of the [[US Department of Agriculture]] at [[Peoria, Illinois]], where facilities for large-scale fermentations were established.<ref name=":12">{{Cite web|vauthors=Carroll A|date=2014-06-02|title=Here is Where: Penicillin Comes to Peoria|url=https://www.historynet.com/here-is-where-penicillin-comes-to-peoria.htm|access-date=2021-01-04|website=HistoryNet|language=en-US|archive-date=2021-01-07|archive-url=https://web.archive.org/web/20210107164913/https://www.historynet.com/here-is-where-penicillin-comes-to-peoria.htm|url-status=live}}</ref><ref name=":2" /> Mass culture of the mould and search for better moulds immediately followed.<ref name=":10" />

On 14 March 1942 the first patient was treated for streptococcal sepsis with US-made penicillin produced by [[Merck & Co.]]<ref name="pmid18626052">{{cite journal | vauthors = Grossman CM | title = The first use of penicillin in the United States | journal = Annals of Internal Medicine | volume = 149 | issue = 2 | pages = 135–36 | date = July 2008 | pmid = 18626052 | doi = 10.7326/0003-4819-149-2-200807150-00009 | s2cid = 40197907 }}</ref> Half of the total supply produced at the time was used on that one patient, Anne Miller.<ref>{{cite magazine|url=https://time.com/4250235/penicillin-1942-history/|title=Penicillin history: what happened to first American patient|magazine=[[Time (magazine)|Time]]|date=14 March 2016|vauthors=Rothman L|access-date=12 March 2019|archive-date=17 March 2019|archive-url=https://web.archive.org/web/20190317151512/http://time.com/4250235/penicillin-1942-history/|url-status=live}}</ref> By June 1942, just enough US penicillin was available to treat ten patients.<ref>{{cite web |vauthors=Mailer JS, Mason B |url=http://www.lib.niu.edu/2001/iht810139.html |title=Penicillin: Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois |publisher=lib.niu.edu |access-date=February 11, 2008 |archive-date=October 7, 2018 |archive-url=https://web.archive.org/web/20181007082158/http://www.lib.niu.edu/2001/iht810139.html |url-status=live }}</ref> In July 1943 the [[War Production Board]] drew up a plan for the mass distribution of penicillin stocks to [[Allies of World War II|Allied]] troops fighting in Europe.<ref name="JParas" /> The results of fermentation research on [[corn steep liquor]] at the NRRL allowed the United States to produce 2.3&nbsp;million doses in time for the [[invasion of Normandy]] in the spring of 1944. After a worldwide search in 1943, a mouldy [[cantaloupe]] in a [[Peoria, Illinois]] market was found to contain the best strain of mould for production using the corn steep liquor process.<ref>{{Cite web |title=The History of Penicillin and Antibiotics |url=https://www.thoughtco.com/history-of-penicillin-1992304 |access-date=2024-06-09 |website=ThoughtCo |language=en |archive-date=2023-04-08 |archive-url=https://web.archive.org/web/20230408215937/https://www.thoughtco.com/history-of-penicillin-1992304 |url-status=live }}</ref> Six times as much penicillin could be produced compared to using Fleming's mould.<ref name=":2" /> [[Jasper H. Kane]], a scientist at [[Pfizer]], suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin.<ref name="Lehrer2006">{{cite book| vauthors = Lehrer S |title=Explorers of the Body: Dramatic Breakthroughs in Medicine from Ancient Times to Modern Science|date=2006|publisher=iUniverse|location=New York|isbn=978-0-595-40731-6|pages=329–30|edition=2nd}}</ref><ref name="Greenwood_2008" />{{rp|109}} Large-scale production resulted from the development of a deep-tank fermentation plant by the chemical engineer [[Margaret Hutchinson Rousseau]].<ref name="Madhavan">{{cite book|vauthors=Madhavan G|title=Think Like an Engineer|date=Aug 20, 2015|publisher=Oneworld Publications|isbn=978-1-78074-637-1|pages=83–85, 91–93|url=https://books.google.com/books?id=GNAfCgAAQBAJ&pg=PT44|access-date=20 November 2016|archive-date=23 March 2017|archive-url=https://web.archive.org/web/20170323204621/https://books.google.com/books?id=GNAfCgAAQBAJ&pg=PT44|url-status=live}}</ref> As a direct result of the war and the War Production Board, by June 1945 over 646&nbsp;billion units per year were being produced.<ref name="JParas">{{cite book| vauthors = Parascandola J |author-link=John Parascandola |title=The History of antibiotics: a symposium| publisher=American Institute of the History of Pharmacy No. 5 |year=1980 |isbn=978-0-931292-08-8 }}</ref>

[[G. Raymond Rettew]] made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin, wherein he combined his knowledge of mushroom spawn with the function of the Sharples Cream Separator.<ref>{{cite web|title=G. Raymond Rettew Historical Marker|url=http://explorepahistory.com/hmarker.php?markerId=1-A-2F2|website=ExplorePAhistory.com|access-date=June 27, 2019|archive-date=January 5, 2020|archive-url=https://web.archive.org/web/20200105212951/http://explorepahistory.com/hmarker.php?markerId=1-A-2F2|url-status=live}}</ref> By 1943 Rettew's lab was producing most of the world's penicillin. During the [[Second World War]] penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces, saving an estimated 12–15% of lives.<ref>{{Cite journal|vauthors=Goyotte D|date=2017|title=The Surgical Legacy of World War II. Part II: The age of antibiotics|url=https://www.ast.org/ceonline/articles/402/files/assets/common/downloads/publication.pdf|journal=The Surgical Technologist|volume=109|pages=257–64|via=|access-date=2021-01-08|archive-date=2021-05-05|archive-url=https://web.archive.org/web/20210505180530/https://www.ast.org/ceonline/articles/402/files/assets/common/downloads/publication.pdf|url-status=live}}</ref> Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid [[clearance (medicine)|renal clearance]] of the drug, necessitating frequent dosing. Methods for mass production of penicillin were patented by [[Andrew Jackson Moyer]] in 1945.<ref>{{cite patent | country = US | number = 2442141 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 25 March 1948 }}</ref><ref>{{cite patent | country = US | number = 2443989 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 22 June 1948 }}</ref><ref>{{cite patent | country = US | number = 2476107 | inventor = Moyer AJ | assign1 = US Agriculture | title = Method for Production of Penicillin | gdate = 12 July 1949 }}</ref> Florey had not patented penicillin, having been advised by Sir [[Henry Hallett Dale|Henry Dale]] that doing so would be unethical.<ref name="SW">{{cite web | title = Making Penicillin Possible: Norman Heatley Remembers | access-date = 2007-02-13 | year = 2007 | work = ScienceWatch | publisher = [[Thomson Scientific]]| url=http://www.sciencewatch.com/interviews/norman_heatly.htm | archive-url= https://web.archive.org/web/20070221041204/http://www.sciencewatch.com/interviews/norman_heatly.htm| archive-date=February 21, 2007}}</ref>

Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused.<ref name=Silverthorn2004>{{cite book | vauthors=Silverthorn DU | title=Human physiology: an integrated approach. | edition=3rd | location=Upper Saddle River (NJ) | publisher=Pearson Education | year=2004 | isbn=978-0-8053-5957-2 | url-access=registration | url=https://archive.org/details/humanphysiology00deeu }}</ref> This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The [[uricosuric]] agent [[probenecid]] proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined.<ref name=Silverthorn2004 /> Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.<ref>{{cite journal | vauthors = Luque Paz D, Lakbar I, Tattevin P | title = A review of current treatment strategies for infective endocarditis | journal = Expert Review of Anti-Infective Therapy | volume = 19 | issue = 3 | pages = 297–307 | date = March 2021 | pmid = 32901532 | doi = 10.1080/14787210.2020.1822165 | s2cid = 221572394 }}</ref>

After the Second World War Australia was the first country to make the drug available for civilian use. In the United States penicillin was made available to the general public on 15 March 1945.<ref name="DR">{{cite web | url = http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html | title = Discovery and development of penicillin | publisher = [[American Chemical Society]] | year = 1999 | access-date = 2015-01-04 | archive-date = 2015-01-03 | archive-url = https://web.archive.org/web/20150103210448/http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html | url-status = live }}</ref>

Fleming, Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the development of penicillin.

<gallery widths="200px" heights="200px">
File:Penicillin Past, Present and Future- the Development and Production of Penicillin, England, 1943 D16959.jpg|A technician preparing penicillin in 1943.
File:PenicillinPSAedit.jpg|Penicillin was being mass-produced in 1944.
File:Penicillin poster 5.40.tif|Second World War poster extolling use of penicillin.
File:Dorothy Hodgkin Nobel.jpg|[[Dorothy Hodgkin]] determined the chemical structure of penicillin.
</gallery>

=== Structure determination and total synthesis ===
[[File:Molecular model of Penicillin by Dorothy Hodgkin (9663803982).jpg|thumb|Dorothy Hodgkin's model of penicillin's structure]]
The [[chemical structure]] of penicillin was first proposed by [[Edward Abraham]] in 1942<ref name=":0">{{Cite journal|vauthors=Jones DS, Jones JH|date=2014-12-01|title=Sir Edward Penley Abraham CBE. 10 June 1913 – 9 May 1999|url=http://rsbm.royalsocietypublishing.org/content/60/5.1|journal=Biographical Memoirs of Fellows of the Royal Society|volume=60|pages=5–22|doi=10.1098/rsbm.2014.0002|s2cid=71557916|issn=0080-4606|doi-access=|access-date=10 May 2017|archive-date=26 November 2023|archive-url=https://web.archive.org/web/20231126055623/http://rsbm.royalsocietypublishing.org/content/60/5.1|url-status=live|url-access=subscription}}</ref> and was later confirmed in 1945 using [[X-ray crystallography]] by [[Dorothy Hodgkin|Dorothy Crowfoot Hodgkin]], who was also working at Oxford.<ref>{{cite web |title=The Nobel Prize in Chemistry 1964 |url=https://www.nobelprize.org/prizes/chemistry/1964/perspectives/ |website=NobelPrize.org |access-date=9 May 2022 |archive-url=https://web.archive.org/web/20170716001027/http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1964/perspectives.html |archive-date=2017-07-16}}</ref> She later in 1964 received the Nobel Prize in Chemistry for this and other structure determinations.

The chemist [[John C. Sheehan]] at the [[Massachusetts Institute of Technology]] (MIT) completed the first chemical [[total synthesis|synthesis]] of penicillin in 1957.<ref name=Sheehan1957>{{cite journal| vauthors = Sheehan JC, Henery-Logan KR |title=The Total Synthesis of Penicillin V|journal=Journal of the American Chemical Society|date=March 5, 1957|volume=79|issue=5|pages=1262–63|doi=10.1021/ja01562a063|bibcode=1957JAChS..79.1262S }}</ref><ref name=Sheehan1959>{{cite journal| vauthors = Sheehan JC, Henery-Loganm KR |title=The Total Synthesis of Penicillin V|journal=Journal of the American Chemical Society|date=June 20, 1959|volume=81|issue=12|pages=3089–94|doi=10.1021/ja01521a044|bibcode=1959JAChS..81.3089S }}</ref><ref name=NAPSheehan>{{cite web|title=Biographical Memoirs: John Clark Sheehan|url=http://www.nap.edu/readingroom.php?book=biomems&page=jsheehan.html|publisher=The National Academy Press|access-date=January 28, 2013|vauthors=Corey EJ, Roberts JD|author-link1=Elias James Corey|author-link2=John D. Roberts|archive-date=March 3, 2016|archive-url=https://web.archive.org/web/20160303213006/http://www.nap.edu/readingroom.php?book=biomems|url-status=live}}</ref> Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of [[peptides]], as well as new [[protecting group]]s—groups that mask the reactivity of certain functional groups.<ref name=NAPSheehan /><ref name=ArtTotalSyn>{{cite journal | vauthors = Nicolaou KC, Vourloumis D, Winssinger N, Baran PS | title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century | journal = Angewandte Chemie | volume = 39 | issue = 1 | pages = 44–122 | date = January 2000 | pmid = 10649349 | doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | author-link4 = Phil S. Baran | author-link1 = K. C. Nicolaou }}</ref> Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehan's synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin.<ref name="Sheehan1957" /><ref name="Sheehan1959" /><ref name=NAPSheehan /><ref name=MITSheehan>{{cite news|title=Professor John C. Sheehan Dies at 76|url=http://web.mit.edu/newsoffice/1992/sheehan-0401.html|access-date=January 28, 2013|newspaper=MIT News|date=April 1, 1992|archive-date=June 30, 2008|archive-url=https://web.archive.org/web/20080630091223/http://web.mit.edu/newsoffice/1992/sheehan-0401.html|url-status=live}}</ref>

6-APA was discovered by researchers at the Beecham Research Laboratories (later the [[Beecham Group]]) in Surrey in 1957 (published in 1959).<ref>{{cite journal | vauthors = Batchelor FR, Doyle FP, Nayler JH, Rolinson GN | title = Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentations | journal = Nature | volume = 183 | issue = 4656 | pages = 257–58 | date = January 1959 | pmid = 13622762 | doi = 10.1038/183257b0 | s2cid = 4268993 | bibcode = 1959Natur.183..257B }}</ref> Attaching different groups to the 6-APA 'nucleus' of penicillin allowed the creation of new forms of penicillins which are more versatile and better in activity.<ref>{{cite journal | vauthors = Rolinson GN, Geddes AM | title = The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA) | journal = International Journal of Antimicrobial Agents | volume = 29 | issue = 1 | pages = 3–8 | date = January 2007 | pmid = 17137753 | doi = 10.1016/j.ijantimicag.2006.09.003 }}</ref>

=== Developments from penicillin ===
The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance).

The first major development was ampicillin in 1961. It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA) strains that subsequently emerged.<ref>{{cite journal | vauthors = Colley EW, Mcnicol MW, Bracken PM | title = Methicillin-Resistant Staphylococci in a General Hospital | journal = Lancet | volume = 1 | issue = 7385 | pages = 595–97 | date = March 1965 | pmid = 14250094 | doi = 10.1016/S0140-6736(65)91165-7 }}</ref>

Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems, and, most importantly, the cephalosporins, still retain it at the center of their structures.<ref>{{cite journal | vauthors = James CW, Gurk-Turner C | title = Cross-reactivity of beta-lactam antibiotics | journal = Proceedings | volume = 14 | issue = 1 | pages = 106–07 | date = January 2001 | pmid = 16369597 | pmc = 1291320 | doi = 10.1080/08998280.2001.11927741 }}</ref>

== Production ==
[[File:Penicillin bioreactor.jpg|thumb|left|A 1957 fermentor (bioreactor) used to grow ''Penicillium'' mould]]

Penicillin is produced by the fermentation of various types of sugar by the fungus ''[[Penicillium rubens]]''.<ref name=":16">{{cite book | vauthors = Kosalková K, Sánchez-Orejas IC, Cueto L, García-Estrada C | chapter = Penicillium chrysogenum Fermentation and Analysis of Benzylpenicillin by Bioassay and HPLC |date=2021 | title = Antimicrobial Therapies | series = Methods in Molecular Biology |volume=2296 |pages=195–207 | veditors = Barreiro C, Barredo JL |place=New York, NY |publisher=Springer US |language=en |doi=10.1007/978-1-0716-1358-0_11 | pmid = 33977449 |isbn=978-1-0716-1357-3 }}</ref> The fermentation process produces penicillin as a [[secondary metabolite]] when the growth of the fungus is inhibited by stress.<ref name=":16" /> The biosynthetic pathway outlined below experiences [[Enzyme inhibitor|feedback inhibition]] involving the by-product {{Smallcaps|l}}-lysine inhibiting the enzyme [[homocitrate synthase]].<ref>{{cite journal | vauthors = Luengo JM, Revilla G, López MJ, Villanueva JR, Martín JF | title = Inhibition and repression of homocitrate synthase by lysine in Penicillium chrysogenum | journal = Journal of Bacteriology | volume = 144 | issue = 3 | pages = 869–76 | date = December 1980 | pmid = 6777369 | pmc = 294747 | doi = 10.1128/jb.144.3.869-876.1980 }}</ref>

:: [[alpha-Ketoglutaric acid|α-ketoglutarate]] + [[Acetyl-CoA|AcCoA]] → [[Homocitric acid|homocitrate]] → [[alpha-Aminoadipic acid|<small>L</small>-α-aminoadipic acid]] → [[Lysine|<small>L</small>-lysine]] + [[Beta-lactam|β-lactam]]

The ''Penicillium'' cells are grown using a technique called [[fed-batch]] culture, in which the cells are constantly subjected to stress, which is required for induction of penicillin production. While the usage of [[glucose]] as a carbon source represses penicillin biosynthesis enzymes, [[lactose]] does not exert any effect and alkaline [[pH]] levels override this regulation. Excess [[phosphate]], available [[oxygen]], and usage of [[ammonium]] as a [[nitrogen]] source repress penicillin production, while [[methionine]] can act as a sole nitrogen/sulfur source with stimulating effects.<ref>{{cite journal | vauthors = Ozcengiz G, Demain AL | title = Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation | journal = Biotechnology Advances | volume = 31 | issue = 2 | pages = 287–311 | date = 2013-03-01 | pmid = 23228980 | doi = 10.1016/j.biotechadv.2012.12.001 | hdl = 11511/46869 | hdl-access = free }}</ref>

The [[Biotechnology|biotechnological]] method of [[directed evolution]] has been applied to produce by mutation a large number of ''Penicillium'' strains. These techniques include [[Polymerase chain reaction|error-prone PCR]], [[DNA shuffling]], [[Protein engineering#Incremental truncation for the creation of hybrid enzymes (ITCHY)|ITCHY]] and [[overlap extension polymerase chain reaction|strand-overlap PCR]].

=== Biosynthesis ===
[[File:Penicillin-biosynthesis.png|class=skin-invert-image|thumb|upright=1.2|Penicillin G biosynthesis]]

The biosynthetic gene cluster for penicillin was first cloned and sequenced in 1990.<ref name="l151">{{cite journal | vauthors = Díez B, Gutiérrez S, Barredo JL, van Solingen P, van der Voort LH, Martín JF | title = The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes | journal = The Journal of Biological Chemistry | volume = 265 | issue = 27 | pages = 16358–16365 | date = September 1990 | pmid = 2129535 | doi = 10.1016/S0021-9258(17)46231-4 | doi-access = free }}</ref> Overall, there are three main and important steps to the biosynthesis of [[penicillin G]] (benzylpenicillin).

* The first step is the condensation of three amino acids—<small>L</small>-α-aminoadipic acid, <small>L</small>-cysteine, <small>L</small>-valine into a [[tripeptide]].<ref name ="Regulation">{{cite book| title = Molecular Biotechnology of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases| volume = 88| veditors = Brakhage AA | vauthors = Al-Abdallah Q, Brakhage AA, Gehrke A, Plattner H, Sprote P, Tuncher A| chapter = Regulation of Penicillin Biosynthesis in Filamentous Fungi| year = 2004| issue = 88| pages = 45–90| doi = 10.1007/b99257| pmid = 15719552| isbn = 978-3-540-22032-9| series = Advances in Biochemical Engineering/Biotechnology}}</ref><ref name=Molecular>{{cite journal | vauthors = Brakhage AA | title = Molecular regulation of beta-lactam biosynthesis in filamentous fungi | journal = Microbiology and Molecular Biology Reviews | volume = 62 | issue = 3 | pages = 547–85 | date = September 1998 | pmid = 9729600 | pmc = 98925 | doi = 10.1128/MMBR.62.3.547-585.1998 }}</ref><ref>{{cite journal | vauthors = Schofield CJ, Baldwin JE, Byford MF, Clifton I, Hajdu J, Hensgens C, Roach P | title = Proteins of the penicillin biosynthesis pathway | journal = Current Opinion in Structural Biology | volume = 7 | issue = 6 | pages = 857–64 | date = December 1997 | pmid = 9434907 | doi = 10.1016/s0959-440x(97)80158-3 }}</ref> Before condensing into the tripeptide, the amino acid <small>L</small>-valine must undergo epimerization to become <small>D</small>-valine.<ref name=Fern>{{cite journal | vauthors = Martín JF, Gutiérrez S, Fernández FJ, Velasco J, Fierro F, Marcos AT, Kosalkova K | title = Expression of genes and processing of enzymes for the biosynthesis of penicillins and cephalosporins | journal = Antonie van Leeuwenhoek | volume = 65 | issue = 3 | pages = 227–43 | date = September 1994 | pmid = 7847890 | doi = 10.1007/BF00871951 | s2cid = 25327312 }}</ref><ref>{{cite journal | vauthors = Baker WL, Lonergan GT | title = Chemistry of some fluorescamine–amine derivatives with relevance to the biosynthesis of benzylpenicillin by fermentation. | journal = Journal of Chemical Technology & Biotechnology | date = December 2002 | volume = 77 | issue = 12 | pages = 1283–88 | doi = 10.1002/jctb.706 | bibcode = 2002JCTB...77.1283B }}</ref> The condensed tripeptide is named δ-(<small>L</small>-α-aminoadipyl)-<small>L</small>-cysteine-<small>D</small>-valine (ACV). The condensation reaction and epimerisation are both catalysed by the enzyme δ-(<small>L</small>-α-aminoadipyl)-<small>L</small>-cysteine-<small>D</small>-valine synthetase (ACVS), a [[nonribosomal peptide]] synthetase or NRPS.
* The second step in the biosynthesis of penicillin G is the [[Redox|oxidative]] conversion of linear ACV into the [[Bicyclic molecule|bicyclic]] intermediate isopenicillin N by [[isopenicillin N synthase]] (IPNS), which is encoded by the gene ''pcbC''.<ref name ="Regulation" /><ref name=Molecular /> Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.<ref name=Fern />
* The final step is a [[transamidation]] by [[isopenicillin N N-acyltransferase]], in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a [[Phenylacetic acid|phenylacetyl]] side-chain. This reaction is encoded by the gene ''penDE'', which is unique in the process of obtaining penicillins.<ref name ="Regulation" />

== See also ==
* [[Medicinal fungi]]
* [[Beta-lactamase]]

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin}}
* {{Cite journal |vauthors=Dürckheimer W, Blumbach J, Lattrell R, Scheunemann KH |date=March 1, 1985 |title=Recent Developments in the Field of β-Lactam Antibiotics |journal=Angewandte Chemie International Edition in English |volume=24 |issue=3 |pages=180–202 |doi=10.1002/anie.198501801}}
* Greenwood, David. ''Antimicrobial Drugs: Chronicle of a twentieth century medical triumph'' (Oxford University Press, 2008) [https://global.oup.com/academic/product/antimicrobial-drugs-9780199534845?cc=us&lang=en&# summary] 

* {{Cite journal |vauthors=Hamed RB, Gomez-Castellanos JR, Henry L, Ducho C, McDonough MA, Schofield CJ |author-link6=Christopher J. Schofield |date=January 2013 |title=The eEnzymes of β-lactam Biosynthesis |journal=Natural Product Reports |volume=30 |issue=1 |pages=21–107 |doi=10.1039/c2np20065a |pmid=23135477}}
* {{Cite book |vauthors=Lax E |year=2004 |title=The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle |publisher=Henry Holt and Co. |isbn=978-0-8050-6790-3}}
* {{Cite book |vauthors=Nicolaou KC, Corey EJ |author-link1=K. C. Nicolaou |author-link2=Elias James Corey |year=1996 |title=Classics in Total Synthesis: Targets, Strategies, Methods |edition=5th repr. |location=Weinheim, Germany |publisher=VCH |isbn=978-3-527-29284-4}}
{{Refend}}

== External links ==
{{Commons category|Penicillin antibiotics}}
* [https://web.archive.org/web/20090327130138/http://users.ox.ac.uk/~jesu1458/ Model of Structure of Penicillin], by Dorothy Hodgkin et al., Museum of the History of Science, Oxford
* {{YouTube|7qeZLLhx5kU|The Discovery of Penicillin, A government-produced film about the discovery of Penicillin by Sir Alexander Fleming, and the continuing development of its use as an antibiotic by Howard Florey and Ernst Boris Chain}}.
* [http://www.periodicvideos.com/videos/mv_penicillin.htm Penicillin] at ''[[The Periodic Table of Videos]]'' (University of Nottingham)
* [https://books.google.com/books?id=PN8DAAAAMBAJ&pg=PA47 "Penicillin Released to Civilians Will Cost $35 Per Patient"], ''[[Popular Science]]'', August 1944, article at bottom of page
* [https://www.pbs.org/video/medical-drugs-l6tio9/ Episode 2 (of 4): "Medical Drugs"] of the [[BBC Four]] and [[PBS]] show: [https://www.nutopia.com/projects/extra-life-a-short-history-of-living-longer ''Extra Life: A Short History of Living Longer''] (2021)

{{PenicillinAntiBiotics}}
{{GABAergics}}
{{Authority control}}

[[Category:Penicillins| ]]
[[Category:1928 in biology]]
[[Category:Drugs developed by Eli Lilly and Company]]
[[Category:GABAA receptor negative allosteric modulators]]
[[Category:Hepatotoxins]]
[[Category:Penicillium]]
[[Category:Drugs developed by Pfizer]]
[[Category:Science and technology during World War II]]
[[Category:Scottish inventions]]
[[Category:Secondary metabolites]]