View source for Beta-lactamase

{{Short description|Class of enzymes}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Use dmy dates|date=September 2020}}
{{Infobox protein family
| Symbol = β-lactamase domain
| Name = Serine beta-lactamase
| image = PDB_1bsg_EBI.jpg
| width = 300px
| caption = Structure of ''[[Streptomyces albus]]'' beta-lactamase
| Pfam = PF00144
| Pfam_clan = CL0013
| InterPro = IPR001466
| SMART =
| PROSITE = PS00146
| MEROPS =
| SCOP = 56601
| TCDB =
| OPM family =
| OPM protein =
| PDB = {{PDB2|1axb}}, {{PDB2|1blp}}, {{PDB2|1bsg}}, {{PDB2|1bue}}, {{PDB2|1e25}}, {{PDB2|1ghi}}, {{PDB2|1i2s}}, {{PDB2|1n9b}}, {{PDB2|1ong}}, {{PDB2|2cc1}}, {{PDB2|2gdn}}, {{PDB2|3dwz}}
}}
{{Infobox protein family
|Name=Metallo-beta-lactamase
| image = 5evb.jpg
| width = 300px
| caption = Metallo-beta-lactamase L1 homotetramer, Stenotrophomonas
|Pfam=PF00753
|Pfam_clan=CL0381
|InterPro=IPR001279
}}
{{infobox enzyme
| Name       = β-lactamase
| EC_number  = 3.5.2.6
| CAS_number = 9073-60-3
| GO_code    = 0008800
| image      = Lactamase Application V.1.svg
| width      = 300px
| caption    = Action of β-lactamase and [[decarboxylation]] of the intermediate
}}
[[Image:Beta-lactam antibiotics example 1.svg|thumb|Core structure of [[penicillin]]s (top) and [[cephalosporin]]s (bottom). [[Beta-lactam]] ring in red.]]
[[Image:ESBL Stokes.jpg|right|thumb|''[[Escherichia coli]]'' bacteria on the right are sensitive to two beta-lactam antibiotics, and do not grow in the semi-circular regions surrounding antibiotics. ''E. coli'' bacteria on the left are resistant to beta-lactam antibiotics, and grow next to one antibiotic (bottom) and are less inhibited by another antibiotic (top).]]

'''Beta-lactamases''' ('''β-lactamases''')  are [[enzyme]]s ({{EC number|3.5.2.6}}) produced by [[bacteria]] that provide [[Multiple drug resistance|multi-resistance]] to [[beta-lactam antibiotic]]s such as [[penicillin]]s, [[cephalosporin]]s, [[cephamycin]]s, [[monobactams]] and [[carbapenem]]s ([[ertapenem]]), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the [[antibiotic]]s' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a [[beta-lactam]] (β-lactam) ring. Through [[hydrolysis]], the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties. 

Beta-lactamases produced by [[gram-negative bacteria]] are usually secreted, especially when antibiotics are present in the environment.<ref name="pmid4894721">{{cite journal | title = Past and Present Perspectives on β-Lactamases | journal = Antimicrobial Agents and Chemotherapy | date = 2018 | volume = 62 | issue = 10 | article-number = e01076-18 | doi = 10.1128/aac.01076-18 | pmid = 30061284 | pmc = 6153792 | vauthors = Bush K }}</ref>

== Structure ==

The structure of a ''[[Streptomyces]]'' serine β-lactamase (SBLs) is given by {{PDB link|1BSG}}. The alpha-beta fold ({{InterPro|IPR012338}}) resembles that of a [[DD-Transpeptidase|<small>DD</small>-transpeptidase]], from which the enzyme is thought to have evolved. β-lactam antibiotics bind to <small>DD</small>-transpeptidases to inhibit bacterial cell wall biosynthesis. Serine β-lactamases are grouped by sequence similarity into types A, C, and D.

The other type of beta-lactamase is of the metallo type ("type B"). Metallo-beta-lactamases (MBLs) need metal ion(s) (1 or 2 Zn<sup>2+</sup> ions<ref name=":0">{{cite journal | vauthors = Rotondo CM, Wright GD | title = Inhibitors of metallo-β-lactamases | journal = Current Opinion in Microbiology | volume = 39 | pages = 96–105 | date = October 2017 | pmid = 29154026 | doi = 10.1016/j.mib.2017.10.026 }}</ref>) on their active site for their catalytic activities.<ref>{{cite journal | vauthors = Shi C, Chen J, Kang X, Shen X, Lao X, Zheng H | title = Approaches for the discovery of metallo-β-lactamase inhibitors: A review | journal = Chemical Biology & Drug Design | volume = 94 | issue = 2 | pages = 1427–1440 | date = August 2019 | pmid = 30925023 | doi = 10.1111/cbdd.13526 | s2cid = 85566136 }}</ref> The structure of the [[New Delhi metallo-beta-lactamase 1]] is given by {{PDB link|6C89}}. It resembles a [[RNase Z]], from which it is thought to have evolved.

== Mechanism of action ==
The two types of beta-lactamases work on the basis of the two basic mechanisms of opening the β-lactam ring.<ref name=":0" />

The SBLs are similar in structure and mechanistically to the β-lactam target penicillin-binding proteins (PBPs) which are necessary for cell wall building and modifying. SBLs and PBPs both covalently change an active site serine residue. The difference between the PBPs and SBLs is that the latter generates free enzyme and inactive antibiotic by the very quick hydrolysis of the acyl-enzyme intermediate.{{citation needed|date=March 2023}}

The MBLs use the Zn<sup>2+</sup> ions to activate a binding site water molecule for the hydrolysis of the β-lactam ring. Zinc chelators have recently been investigated as metallo-β-lactamase inhibitors, as they are often able to restore carbapenem susceptibility.<ref>{{Cite journal |last1=Principe |first1=Luigi |last2=Vecchio |first2=Graziella |last3=Sheehan |first3=Gerard |last4=Kavanagh |first4=Kevin |last5=Morroni |first5=Gianluca |last6=Viaggi |first6=Valentina |last7=di Masi |first7=Alessandra |last8=Giacobbe |first8=Daniele Roberto |last9=Luzzaro |first9=Francesco |last10=Luzzati |first10=Roberto |last11=Di Bella |first11=Stefano |date=2020-10-01 |title=Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation |url=https://www.liebertpub.com/doi/10.1089/mdr.2020.0037 |journal=Microbial Drug Resistance |language=en |volume=26 |issue=10 |pages=1133–1143 |doi=10.1089/mdr.2020.0037 |pmid=32364820 |s2cid=218504647 |issn=1076-6294|url-access=subscription }}</ref>

== Penicillinase ==
Penicillinase is a specific type of β-lactamase, showing specificity for [[penicillin]]s, again by [[hydrolysis|hydrolysing]] the [[β-lactam]] ring.  Molecular weights of the various penicillinases tend to cluster near 50 kilodaltons.

Penicillinase was the first β-lactamase to be identified. It was first isolated by Abraham and Chain in 1940 from ''E. coli'' (which are gram-negative) even before penicillin entered clinical use,<ref>{{cite journal | title=An enzyme from bacteria able to destroy penicillin | vauthors=Abraham EP, Chain E | journal=Nature | year=1940 | volume=46 | page=837 | doi=10.1038/146837a0 | issue=3713| bibcode=1940Natur.146..837A | s2cid=4070796 | doi-access=free }}</ref> but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely.  Penicillinase-resistant beta-lactams such as [[methicillin]] were developed, but there is now widespread [[antibiotic resistance|resistance]] to even these.

==Resistance in gram-negative bacteria==
{{cleanup section|reason=confusing mix of structural and functional classifications; need explanatory paragraph on what these classes are|date=September 2021}}
Among gram-negative bacteria, the emergence of resistance to extended-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (''[[Enterobacter cloacae|E. cloacae]]'', ''[[Citrobacter freundii|C. freundii]]'', ''[[S. marcescens]]'', and ''[[P. aeruginosa]]'') that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later, resistance appeared in bacterial species not naturally producing AmpC enzymes (''[[K. pneumoniae]]'', ''[[Salmonella]]'' spp., ''[[Proteus mirabilis|P. mirabilis]]'') due to the production of TEM- or SHV-type ESBLs (extended spectrum beta lactamases). Characteristically, such resistance has included oxyimino- (for example [[ceftizoxime]], [[cefotaxime]], [[ceftriaxone]], and [[ceftazidime]], as well as the oxyimino-monobactam [[aztreonam]]), but not 7-alpha-methoxy-cephalosporins ([[cephamycins]]; in other words, [[cefoxitin]] and [[cefotetan]]); has been blocked by inhibitors such as [[clavulanate]], [[sulbactam]] or [[tazobactam]] and did not involve [[carbapenems]] and [[temocillin]]. Chromosomal-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins ([[cephamycins]]) such as [[cefoxitin]] or [[cefotetan]] but are not affected by commercially available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.<ref name="pmid11751104">{{cite journal | vauthors = Philippon A, Arlet G, Jacoby GA | title = Plasmid-determined AmpC-type beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 1 | pages = 1–11 | date = January 2002 | pmid = 11751104 | pmc = 126993 | doi = 10.1128/AAC.46.1.1-11.2002 }}</ref>

===Extended-spectrum beta-lactamase (ESBL)===
Members of this family commonly express β-lactamases (e.g., TEM-3, TEM-4,<ref>{{cite web | title = Ambler class A beta-lactamases: TEM | url = http://bldb.eu/BLDB.php?prot=A#TEM | work = Beta-Lactamase DataBase (BLDB | access-date = 11 February 2022 | archive-date = 11 February 2022 | archive-url = https://web.archive.org/web/20220211114053/http://bldb.eu/BLDB.php?prot=A#TEM | url-status = live }}</ref> and SHV-2 <ref>{{cite web | title = Ambler class A beta-lactamases: SHV | url = http://bldb.eu/BLDB.php?prot=A#SHV | work = Beta-Lactamase DataBase (BLDB) | access-date = 11 February 2022 | archive-date = 11 February 2022 | archive-url = https://web.archive.org/web/20220211114053/http://bldb.eu/BLDB.php?prot=A#SHV | url-status = live }}</ref>) which confer resistance to expanded-spectrum (extended-spectrum) cephalosporins. In the mid-1980s, this new group of enzymes, the extended-spectrum β-lactamases (ESBLs), was detected (first detected in 1979).<ref name="pmid314270">{{cite journal | vauthors = Sanders CC, Sanders WE | title = Emergence of resistance to cefamandole: possible role of cefoxitin-inducible beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 15 | issue = 6 | pages = 792–797 | date = June 1979 | pmid = 314270 | pmc = 352760 | doi = 10.1128/AAC.15.6.792 }}</ref> The prevalence of ESBL-producing bacteria have been gradually increasing in acute care hospitals.<ref>{{cite journal | vauthors = Spadafino JT, Cohen B, Liu J, Larson E | title = Temporal trends and risk factors for extended-spectrum beta-lactamase-producing Escherichia coli in adults with catheter-associated urinary tract infections | journal = Antimicrobial Resistance and Infection Control | volume = 3 | issue = 1 | article-number = 39 | year = 2014 | pmid = 25625011 | pmc = 4306238 | doi = 10.1186/s13756-014-0039-y | doi-access = free }}</ref> The prevalence in the general population varies between countries, e.g. approximately 6% in Germany<ref>{{cite journal | vauthors = Symanzik C, Hillenbrand J, Stasielowicz L, Greie JC, Friedrich AW, Pulz M, John SM, Esser J | title = Novel insights into pivotal risk factors for rectal carriage of extended-spectrum-β-lactamase-producing enterobacterales within the general population in Lower Saxony, Germany | journal = Journal of Applied Microbiology | date = December 2021 | volume = 132 | issue = 4 | pages = 3256–3264 | pmid = 34856042 | doi = 10.1111/jam.15399 | s2cid = 244854840 | url = https://research.rug.nl/en/publications/44470d41-0614-468c-8e02-f1e748aba302 }}</ref> and France,<ref>{{cite journal | vauthors = Nicolas-Chanoine MH, Gruson C, Bialek-Davenet S, Bertrand X, Thomas-Jean F, Bert F, Moyat M, Meiller E, Marcon E, Danchin N, Noussair L, Moreau R, Leflon-Guibout V | title = 10-Fold increase (2006-11) in the rate of healthy subjects with extended-spectrum β-lactamase-producing Escherichia coli faecal carriage in a Parisian check-up centre | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 3 | pages = 562–568 | date = March 2013 | pmid = 23143897 | doi = 10.1093/jac/dks429 }}</ref> 13% in Saudi Arabia,<ref>{{cite journal | vauthors = Kader AA, Kamath KA | title = Faecal carriage of extended-spectrum beta-lactamase-producing bacteria in the community | journal = Eastern Mediterranean Health Journal| volume = 15 | issue = 6 | pages = 1365–1370 | date = 2009 | pmid = 20218126 }}</ref> and 63% in Egypt.<ref>{{cite journal | vauthors = Valverde A, Grill F, Coque TM, Pintado V, Baquero F, Cantón R, Cobo J | title = High rate of intestinal colonization with extended-spectrum-beta-lactamase-producing organisms in household contacts of infected community patients | journal = Journal of Clinical Microbiology | volume = 46 | issue = 8 | pages = 2796–2799 | date = August 2008 | pmid = 18562591 | pmc=2519510 | doi = 10.1128/JCM.01008-08 }}</ref>

ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include [[cefotaxime]], [[ceftriaxone]], and [[ceftazidime]], as well as the oxyimino-monobactam [[aztreonam]]. Thus, ESBLs confer [[Multiple drug resistance|multi-resistance]] to these antibiotics and related oxyimino-beta lactams. In typical circumstances, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. A broader set of β-lactam antibiotics are susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described.<ref name="pmid9230382">{{cite journal | vauthors = Emery CL, Weymouth LA | title = Detection and clinical significance of extended-spectrum beta-lactamases in a tertiary-care medical center | journal = Journal of Clinical Microbiology | volume = 35 | issue = 8 | pages = 2061–2067 | date = August 1997 | pmid = 9230382 | pmc = 229903 | doi = 10.1128/JCM.35.8.2061-2067.1997 }}</ref> The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. [[Carbapenem]]s are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant (primarily [[ertapenem]]-resistant) isolates have recently been reported.<ref name="Grundmann_2010">{{cite journal | vauthors = Grundmann H, Livermore DM, Giske CG, Canton R, Rossolini GM, Campos J, Vatopoulos A, Gniadkowski M, Toth A, Pfeifer Y, Jarlier V, Carmeli Y | title = Carbapenem-non-susceptible Enterobacteriaceae in Europe: conclusions from a meeting of national experts | journal = Euro Surveillance | volume = 15 | issue = 46 | date = November 2010 | pmid = 21144429 | doi = 10.2807/ese.15.46.19711-en | doi-access = free | hdl = 10400.18/206 | hdl-access = free }}</ref> ESBL-producing organisms may appear susceptible to some extended-spectrum [[cephalosporin]]s. However, treatment with such antibiotics has been associated with high failure rates.{{Citation needed|date=December 2015}}

=== Types ===
{{Redirect|Amp resistance|resistance to antimicrobial peptides|AMP resistance}}
==== TEM beta-lactamases (class A) ====
TEM-1 is the most commonly encountered beta-lactamase in [[gram-negative bacteria]]. Up to 90% of ampicillin resistance in [[Escherichia coli|''E. coli'']] is due to the production of TEM-1.<ref name="pmid2193616">{{cite journal | vauthors = Cooksey R, Swenson J, Clark N, Gay E, Thornsberry C | title = Patterns and mechanisms of beta-lactam resistance among isolates of Escherichia coli from hospitals in the United States | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 5 | pages = 739–45 | date = May 1990 | pmid = 2193616 | pmc = 171683 | doi = 10.1128/AAC.34.5.739 }}</ref> Also responsible for the ampicillin and penicillin resistance that is seen in ''[[H. influenzae]]'' and ''[[N. gonorrhoeae]]'' in increasing numbers. Although TEM-type beta-lactamases are most often found in ''[[Escherichia coli|E. coli]]'' and ''[[K. pneumoniae]]'', they are also found in other species of gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the [[#Extended-spectrum beta-lactamase (ESBL)|extended-spectrum beta lactamase (ESBL)]] phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the susceptibility of the enzyme to β-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.<ref name="pmid14576117">{{cite journal | vauthors = Paterson DL, Hujer KM, Hujer AM, Yeiser B, Bonomo MD, Rice LB, Bonomo RA | title = Extended-spectrum beta-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3554–60 | date = November 2003 | pmid = 14576117 | pmc = 253771 | doi = 10.1128/AAC.47.11.3554-3560.2003 }}</ref><ref name="pmid11585791">{{cite journal | vauthors = Bradford PA | title = Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat | journal = Clinical Microbiology Reviews | volume = 14 | issue = 4 | pages = 933–51, table of contents | date = October 2001 | pmid = 11585791 | pmc = 89009 | doi = 10.1128/CMR.14.4.933-951.2001 }}</ref><ref name="pmid15673804">{{cite journal | vauthors = Jacoby GA, Munoz-Price LS | title = The new beta-lactamases | journal = The New England Journal of Medicine | volume = 352 | issue = 4 | pages = 380–91 | date = January 2005 | pmid = 15673804 | doi = 10.1056/NEJMra041359 }}</ref> The term TEM comes from the name of the Athenian patient (Temoniera) from which the isolate was recovered in 1963.<ref>{{cite journal  | doi = 10.3201/eid2404.et2404 | title = Etymologia: TEM | year = 2018 | vauthors = Ruiz J | journal = Emerging Infectious Diseases | volume = 24 | issue = 4 | page = 709 | doi-access = free | pmc = 5875283 }}</ref>

====SHV beta-lactamases (class A)====
SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in ''[[K. pneumoniae]]'' and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known. SHV-5 and SHV-12 are among the most common.<ref name="pmid14576117"/> The initials stand for "sulfhydryl reagent variable".<ref>{{cite journal | vauthors = Liakopoulos A, Mevius D, Ceccarelli D | title = A Review of SHV Extended-Spectrum β-Lactamases: Neglected Yet Ubiquitous | journal = Frontiers in Microbiology | volume = 7 | page = 1374 | date = 2016-09-05 | pmid = 27656166 | pmc = 5011133 | doi = 10.3389/fmicb.2016.01374 | doi-access = free }}</ref>

==== CTX-M beta-lactamases (class A) ====
These enzymes were named for their greater activity against [[cefotaxime]] than other oxyimino-beta-lactam substrates (e.g., [[ceftazidime]], [[ceftriaxone]], or [[cefepime]]). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of ''[[Kluyvera]]'' species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 172<ref>{{cite journal | vauthors = Ramadan AA, Abdelaziz NA, Amin MA, Aziz RK | title = Novel blaCTX-M variants and genotype-phenotype correlations among clinical isolates of extended spectrum beta lactamase-producing Escherichia coli | journal = Scientific Reports | volume = 9 | issue = 1 | article-number = 4224 | date = March 2019 | pmid = 30862858 | pmc = 6414621 | doi = 10.1038/s41598-019-39730-0 | s2cid = 75136447 | bibcode = 2019NatSR...9.4224R }}</ref> CTX-M enzymes are currently known. Despite their name, a few are more active on [[ceftazidime]] than [[cefotaxime]]. They are widely described among species of [[Enterobacteriaceae]], mainly ''E. coli'' and ''K. pneumoniae''. Detected in the 1980s they have since the early 2000s spread and are the now the predominant ESBL type in the world. They are generally clustred into five groups based on sequencing homologies; CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9 and CTX-M-25.  CTX-M-15 (belonging to the CTX-M-1 cluster) is the most prevalent CTX-M-gene.<ref>{{Cite journal |last=Castanheira |first=Mariana |date=3 Sep 2021 |title=Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection |journal=Journal of Antimicrobial Chemotherapy|volume=3 |issue=3 |article-number=dlab092 |doi=10.1093/jacamr/dlab092 |pmid=34286272 |pmc=8284625 }}</ref> An example of beta-lactamase CTX-M-15, along with IS''Ecp1'', has been found to have transposed onto the chromosome of ''[[Klebsiella pneumoniae]]'' ATCC BAA-2146.<ref>{{cite journal | vauthors = Hudson CM, Bent ZW, Meagher RJ, Williams KP | title = Resistance determinants and mobile genetic elements of an NDM-1-encoding Klebsiella pneumoniae strain | journal = PLOS ONE | volume = 9 | issue = 6 | article-number = e99209 | date = 7 June 2014 | pmid = 24905728 | pmc = 4048246 | doi = 10.1371/journal.pone.0099209 | doi-access = free | bibcode = 2014PLoSO...999209H }}</ref> The initials stand for "Cefotaxime-Munich".<ref>{{Cite journal | vauthors = Cantón R, González-Alba JM, Galán JC |date=2012 |title=CTX-M Enzymes: Origin and Diffusion |journal= Frontiers in Microbiology |volume=3 |page=110 |doi=10.3389/fmicb.2012.00110 |pmid=22485109 |pmc=3316993 |issn=1664-302X|doi-access=free }}</ref>

==== OXA beta-lactamases (class D) ====
OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze [[oxacillin]] and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they belong to molecular class D and functional group 2d. The OXA-type beta-lactamases confer resistance to [[ampicillin]] and [[cephalothin]] and are characterized by their high hydrolytic activity against [[oxacillin]] and [[cloxacillin]] and the fact that they are poorly inhibited by [[clavulanic acid]]. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in ''[[Escherichia coli|E. coli]]'', ''[[K. pneumoniae]]'', and other [[Enterobacteriaceae]], the OXA-type ESBLs have been found mainly in ''[[P. aeruginosa]]''. OXA-type ESBLs have been found mainly in ''[[Pseudomonas aeruginosa]]'' isolates from Turkey and France. The OXA beta-lactamase family was originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime.

==== Others ====
Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and have been found mainly in ''[[P. aeruginosa]]'' and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy; VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece. PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in Enterobacteriaceae.

====Treatment====
While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now increasingly found in the community. CTX-M-15-positive [[Escherichia coli|E. coli]] are a cause of community-acquired [[cystitis|urinary infections]] in the UK,<ref name="Woodford_2006">{{cite web |display-authors=etal |title=Molecular characterisation of ''Escherichia coli'' isolates producing CTX-M-15 extended-spectrum β-lactamase (ESBL) in the United Kingdom |url=http://www.hpa.org.uk/cfi/armrl/ARMRL_posters/Woodford%20ECCMID%202004%20poster.pdf |archive-url=https://web.archive.org/web/20070615160527/http://www.hpa.org.uk/cfi/armrl/ARMRL_posters/Woodford%20ECCMID%202004%20poster.pdf |archive-date=15 June 2007 |access-date=2006-11-19 |publisher=Health Protection Agency |vauthors=Woodford N, Ward E, Kaufmann ME}}</ref> and tend to be resistant to all oral β-lactam antibiotics, as well as [[quinolone antibiotic|quinolones]] and [[sulfonamide (medicine)|sulfonamide]]s. Treatment options may include [[nitrofurantoin]], [[fosfomycin]], [[mecillinam]] and [[chloramphenicol]].  In desperation, once-daily [[ertapenem]] or [[gentamicin]] injections may also be used.

=== Inhibitor-resistant β-lactamases ===
Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of ''[[Escherichia coli|E. coli]]'', but also some strains of ''[[K. pneumoniae]]'', ''[[Klebsiella oxytoca]]'', ''[[Proteus mirabilis|P. mirabilis]]'', and ''[[Citrobacter freundii]]''. Although the inhibitor-resistant TEM variants are resistant to inhibition by [[clavulanic acid]] and [[sulbactam]], thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of [[amoxicillin]]-[[clavulanate]] ([[co-amoxiclav]]), [[ticarcillin]]-[[clavulanate]] ([[co-ticarclav]]), and [[ampicillin/sulbactam]], they normally remain susceptible to inhibition by [[tazobactam]] and subsequently the combination of [[piperacillin/tazobactam]],{{Citation needed|reason=Reliable source needed for the tazobactam susceptibility, as source n°4 states otherwise|date=November 2014}} although resistance has been described. This is no longer a primarily European epidemiology, it is found in northern parts of America often and should be tested for with complex UTI's.<ref name="pmid11585791"/>

===AmpC-type β-lactamases (class C)===
AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant gram-negative bacteria. AmpC β-lactamases (also termed class C or group 1) are typically encoded on the chromosome of many gram-negative bacteria including ''[[Citrobacter]]'', ''[[Serratia]]'' and ''[[Enterobacter]]'' species where its expression is usually [[Regulation of gene expression#Inducible vs. repressible systems|inducible]]; it may also occur on ''[[Escherichia coli]]'' but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.<ref name="pmid11751104"/> AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not typically inhibited by the β-lactamase inhibitors [[clavulanic acid]] and [[tazobactam]], whereas [[avibactam]] can maintain inhibitory activity against this class of β-lactamases.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MedR.pdf |title=Clinical Review, NDA 206494, Ceftazidime-avibactam |publisher=Food and Drug Administration (FDA) |date=2015-02-18 |access-date=14 November 2023 |archive-date=28 February 2017 |archive-url=https://web.archive.org/web/20170228174712/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MedR.pdf }}</ref> AmpC-type β-lactamase organisms are often clinically grouped through the acronym, "SPACE": ''[[Serratia]], [[Pseudomonas]]'' or ''[[Proteus bacteria|Proteus]], [[Acinetobacter]], [[Citrobacter]]'', and ''[[Enterobacter]]''.

==Carbapenemases==
Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases. Carbapenemases are a diverse group of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. Aztreonam is stable to the metallo-β-lactamases,
but many IMP and VIM producers are resistant, owing to other mechanisms.   Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described.

===IMP-type carbapenemases (metallo-β-lactamases) (class B)===
Plasmid-mediated IMP-type carbapenemases (IMP stands for active-on-imipenem), 19 varieties of which are currently known, became established in Japan in the 1990s both in enteric gram-negative organisms and in ''[[Pseudomonas]]'' and ''[[Acinetobacter]]'' species. IMP enzymes spread slowly to other countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil.

===VIM (Verona integron-encoded metallo-β-lactamase) (Class B)===
A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1 was discovered in ''P. aeruginosa'' in Italy in 1996; since then, VIM-2 - now the predominant variant - was found repeatedly in Europe and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively.

Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of both the families, nevertheless, are similar. Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams except monobactams, and evade all β-lactam inhibitors. The VIM enzymes are among the most widely distributed MBLs, with >40 VIM variants having been reported. Biochemical and biophysical studies revealed that VIM variants have only small variations in their kinetic parameters but substantial differences in their thermal stabilities and inhibition profiles.<ref name="Comparison of Verona Integron-Borne">{{cite journal | vauthors = Makena A, Düzgün AÖ, Brem J, McDonough MA, Rydzik AM, Abboud MI, Saral A, Çiçek AÇ, Sandalli C, Schofield CJ | title = Comparison of Verona Integron-Borne Metallo-β-Lactamase (VIM) Variants Reveals Differences in Stability and Inhibition Profiles | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 3 | pages = 1377–84 | date = December 2015 | pmid = 26666919 | pmc = 4775916 | doi = 10.1128/AAC.01768-15 }}</ref>

=== OXA (oxacillinase) group of β-lactamases (class D) ===
The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly ''in vitro'', and the high MICs seen for some Acinetobacter hosts (>64&nbsp;mg/L) may reflect secondary mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or efflux.  OXA carbapenemases also tend to have a reduced hydrolytic efficiency towards penicillins and cephalosporins.<ref name="pmid17374723">{{cite journal | vauthors = Santillana E, Beceiro A, Bou G, Romero A | title = Crystal structure of the carbapenemase OXA-24 reveals insights into the mechanism of carbapenem hydrolysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 13 | pages = 5354–9 | date = March 2007 | pmid = 17374723 | pmc = 1838445 | doi = 10.1073/pnas.0607557104 | doi-access = free | bibcode = 2007PNAS..104.5354S }}</ref>

===KPC (''K. pneumoniae'' carbapenemase) (class A)===
A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Ten variants, KPC-2 through KPC-11 are known, and they are distinguished by one or two [[amino acid]] substitutions (KPC-1 was re-sequenced in 2008 and found to be 100% homologous to published sequences of KPC-2). KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.

{{as of |February 2009}}, the class A ''[[Klebsiella pneumoniae]]'' carbapenemase ([[Klebsiella pneumoniae#Resistant strains|KPC]]) globally has been the most common carbapenemase, and was first detected in 1996 in [[North Carolina]], USA.<ref name="pmid19324295">{{cite journal | vauthors = Nordmann P, Cuzon G, Naas T | title = The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria | journal = The Lancet. Infectious Diseases | volume = 9 | issue = 4 | pages = 228–36 | date = April 2009 | pmid = 19324295 | doi = 10.1016/S1473-3099(09)70054-4 }}</ref> A 2010 publication indicated that KPC producing Enterobacteriaceae were becoming common in the United States.<ref name="pmid19854586">{{cite journal | vauthors = Cuzon G, Naas T, Nordmann P | title = [KPC carbapenemases: what is at stake in clinical microbiology?] | language = fr | journal = Pathologie-Biologie | volume = 58 | issue = 1 | pages = 39–45 | date = February 2010 | pmid = 19854586 | doi = 10.1016/j.patbio.2009.07.026 }}</ref>

===CMY (class C)===
The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of ''Enterobacter aerogenes''.<ref name="pmid16677302">{{cite journal | vauthors = Kim JY, Jung HI, An YJ, Lee JH, Kim SJ, Jeong SH, Lee KJ, Suh PG, Lee HS, Lee SH, Cha SS | title = Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase | journal = Molecular Microbiology | volume = 60 | issue = 4 | pages = 907–16 | date = May 2006 | pmid = 16677302 | doi = 10.1111/j.1365-2958.2006.05146.x | s2cid = 44982704 | doi-access = free }}</ref> It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.<ref name="pmid15383166">{{cite journal | vauthors = Lee JH, Jung HI, Jung JH, Park JS, Ahn JB, Jeong SH, Jeong BC, Lee JH, Lee SH | title = Dissemination of transferable AmpC-type beta-lactamase (CMY-10) in a Korean hospital | journal = Microbial Drug Resistance | volume = 10 | issue = 3 | pages = 224–30 | year = 2004 | pmid = 15383166 | doi = 10.1089/mdr.2004.10.224 }}</ref>

===SME (Serratia marcescens enzymes), IMI (IMIpenem-hydrolysing β-lactamase), NMC and CcrA ===
In general, these enzymes are of limited clinical significance.<ref>{{cite journal |last=Bush |first=K. |last2=Jacoby |first2=G. A. |title=Updated functional classification of beta-lactamases |journal=Antimicrobial Agents and Chemotherapy |year=2010 |volume=54 |issue=3 |pages=969–976 |doi=10.1128/AAC.01009-09}}</ref>
CcrA (also known as CfiA) is encoded by a gene present in approximately 1–3% of Bacteroides fragilis isolates; however, only a subset express the enzyme, as expression generally requires activation by an upstream insertion sequence.<ref>{{cite journal |last=Podglajen |first=I. |last2=Breuil |first2=J. |last3=Collatz |first3=E. |title=Insertion of a novel DNA sequence upstream of the cfiA gene promotes expression of carbapenem resistance in Bacteroides fragilis |journal=Antimicrobial Agents and Chemotherapy |year=1994 |volume=38 |issue=5 |pages=1094–1098 |doi=10.1128/AAC.38.5.1094}}</ref> CcrA-producing strains were identified prior to the clinical introduction of imipenem, and their prevalence has shown little subsequent increase.<ref>{{cite journal |last=Livermore |first=D. M. |title=Beta-lactamases in laboratory and clinical resistance |journal=Clinical Microbiology Reviews |year=1995 |volume=8 |issue=4 |pages=557–584 |doi=10.1128/CMR.8.4.557}}</ref>

===NDM-1 (New Delhi metallo-β-lactamase) (class B)===
{{Main|New Delhi metallo-beta-lactamase}}
Originally described from [[New Delhi]] in 2009, this gene is now widespread in ''[[Escherichia coli]]'' and ''[[Klebsiella pneumoniae]]'' from India and Pakistan. As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the United States and UK), most probably due to the large number of tourists travelling the globe, who may have picked up the strain from the environment, as strains containing the NDM-1 gene have been found in environmental samples in India.<ref name="pmid21478057">{{cite journal | vauthors = Walsh TR, Weeks J, Livermore DM, Toleman MA | title = Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study | journal = The Lancet. Infectious Diseases | volume = 11 | issue = 5 | pages = 355–62 | date = May 2011 | pmid = 21478057 | doi = 10.1016/S1473-3099(11)70059-7 }}</ref> NDM have several variants which share different properties.<ref name="Comparison of Verona Integron-Borne"/>

==Treatment of ESBL/AmpC/carbapenemases==

===General overview===

In general, an isolate is suspected to be an ESBL producer when it shows ''in vitro'' susceptibility to the [[cephamycin]]s ([[cefoxitin]], [[cefotetan]]) but resistance to the third-generation cephalosporins and to [[aztreonam]]. Moreover, one should suspect these strains when treatment with these agents for gram-negative infections fails despite reported ''in vitro'' susceptibility. Once an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam, even if it is tested (in vitro) as susceptible.{{Citation needed|date=August 2010}} Associated resistance to [[aminoglycosides]] and [[trimethoprim]]-[[sulfamethoxazole]], as well as high frequency of co-existence of [[fluoroquinolone]] resistance, creates problems. Beta-lactamase inhibitors such as [[clavulanate]], [[sulbactam]], and [[tazobactam]] ''in vitro'' inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor combinations cannot be relied on consistently for therapy. [[Cephamycins]] ([[cefoxitin]] and [[cefotetan]]) are not hydrolyzed by majority of ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase.  Also, β-lactam/β-lactamase inhibitor combinations may not be effective against organisms that produce AmpC-type β-lactamase.  Sometimes these strains decrease the expression of outer membrane proteins, rendering them resistant to cephamycins. ''In vivo'' studies have yielded mixed results against ESBL-producing ''[[K. pneumoniae]]''. ([[Cefepime]], a fourth-generation cephalosporin, has demonstrated ''in vitro'' stability in the presence of many ESBL/AmpC strains.) Currently, [[carbapenems]] are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent ''in vitro'' activity against strains of [[Enterobacteriaceae]] expressing ESBLs.{{Citation needed|date=August 2010}}

=== According to genes ===

====ESBLs====

Strains producing only ESBLs are susceptible to [[cephamycins]] and [[carbapenems]] ''in vitro'' and show little if any [[inoculum effect]] with these agents.

For organisms producing '''TEM''' and '''SHV''' type ESBLs, apparent ''in vitro'' sensitivity to [[cefepime]] and to [[piperacillin/tazobactam]] is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 10<sup>5</sup> to 10<sup>7</sup> organisms.

Strains with some '''CTX-M'''–type and '''OXA'''-type ESBLs are resistant to [[cefepime]] on testing, despite the use of a standard inoculum.

====Inhibitor-resistant β-lactamases====

Although the inhibitor-resistant TEM variants are resistant to inhibition by [[clavulanic acid]] and [[sulbactam]], thereby showing clinical resistance to the beta-lactam—beta lactamase inhibitor combinations of [[amoxicillin]]-[[clavulanate]] ([[Co-amoxiclav]]), [[ticarcillin]]-[[clavulanate]], and [[ampicillin/sulbactam]], they remain susceptible to inhibition by [[tazobactam]] and subsequently the combination of [[piperacillin/tazobactam]].

====AmpC====

AmpC-producing strains are typically resistant to [[oxyimino-beta lactams]] and to [[cephamycins]] and are susceptible to [[carbapenems]]; however, diminished porin expression can make such a strain carbapenem-resistant as well.

====Carbapenemases====

Strains with '''IMP-, VIM-, and OXA'''-type carbapenemases usually remain susceptible. Resistance to non-beta-lactam antibiotics is common in strains making any of these enzymes, such that alternative options for non-beta-lactam therapy need to be determined by direct susceptibility testing. Resistance to [[fluoroquinolones]] and [[aminoglycosides]] is especially high.

===According to species===

====''Escherichia coli'' or ''Klebsiella''====

For infections caused by ESBL-producing ''[[Escherichia coli]]'' or ''[[Klebsiella]]'' species, treatment with [[imipenem]] or [[meropenem]] has been associated with the best outcomes in terms of survival and bacteriologic clearance. [[Cefepime]] and [[piperacillin/tazobactam]] have been less successful. [[Ceftriaxone]], [[cefotaxime]], and [[ceftazidime]] have failed even more often, despite the organism's susceptibility to the antibiotic ''in vitro''. Several reports have documented failure of [[cephamycin]] therapy as a result of resistance due to porin loss. Some patients have responded to [[aminoglycoside]] or [[Quinolone antibiotic|quinolone]] therapy, but, in a recent comparison of [[ciprofloxacin]] and [[imipenem]] for bacteremia involving an ESBL-producing ''[[K. pneumoniae]]'', [[imipenem]] produced the better outcome

====''Pseudomonas aeruginosa''====

There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing ''[[Pseudomonas aeruginosa]]'' strains.

== Use as a pharmaceutical ==
In 1957, amid concern about allergic reactions to penicillin-containing antibiotics, a beta-lactamase was sold as an antidote under the brand name neutrapen.<ref>{{Cite news|date=1957-10-04|title=NEW DRUG FIGHTS ILLS OF PENICILLIN; Antibiotics Expert Finds Neutrapen Effective on Injection Side Effect ALLERGY RISE STUDIED U.S. Aide Reports Increase in Reaction to Penicillin and Like Substances Severe Reactions Few Some Severe Reactions (Published 1957)|language=en-US|work=The New York Times|url=https://www.nytimes.com/1957/10/04/archives/new-drug-fights-ills-of-penicillin-antibiotics-expert-finds.html|access-date=2020-12-24|issn=0362-4331|archive-date=31 January 2022|archive-url=https://web.archive.org/web/20220131074502/https://www.nytimes.com/1957/10/04/archives/new-drug-fights-ills-of-penicillin-antibiotics-expert-finds.html|url-status=live}}</ref> It was theorized that the breakdown of penicillin by the enzyme would treat the allergic reaction.<ref>{{cite journal | vauthors = Hyman AL | title = Anaphylactic shock after therapy with penicillinase | journal = Journal of the American Medical Association | volume = 169 | issue = 6 | pages = 593–4 | date = February 1959 | pmid = 13620512 | doi = 10.1001/jama.1959.73000230003011a }}</ref> While it was not useful in acute anaphylactic shock, it showed positive results in cases of [[urticaria]] and joint pain suspected to be caused by penicillin allergy.<ref>{{cite journal | vauthors = Friedlaender S | title = Penicillinase in the treatment of allergic reactions to penicillin | journal = Journal of Allergy | volume = 30 | issue = 2 | pages = 181–7 | date = April 1959 | pmid = 13630649 | doi = 10.1016/0021-8707(59)90087-5 }}</ref><ref>{{Cite journal|author=American Academy of Pediatrics|date=1958-10-01|title=A New Concept in the Treatment of Penicillin Reactions: Use of Penicillinase|url=https://pediatrics.aappublications.org/content/22/4/658|journal=Pediatrics|language=en|volume=22|issue=4|page=658|doi=10.1542/peds.22.4.658|s2cid=245066458|issn=0031-4005|access-date=24 December 2020|archive-date=28 September 2018|archive-url=https://web.archive.org/web/20180928095536/http://pediatrics.aappublications.org/content/22/4/658|url-status=live|url-access=subscription}}</ref> Its use was proposed in pediatric cases where penicillin allergy was discovered upon administration of the polio vaccine, which used penicillin as a preservative.<ref>{{cite journal | vauthors = Zimmerman MC | title = Penicillinase-proved allergy to penicillin in poliomyelitis vaccine | journal = Journal of the American Medical Association | volume = 167 | issue = 15 | pages = 1807–9 | date = August 1958 | pmid = 13563181 | doi = 10.1001/jama.1958.02990320001001 }}</ref> However, some patients developed allergies to neutrapen.<ref>{{cite journal | vauthors = Weiss RC, Crepea SB | title = Development of sensitivity to penicillinase following its use in penicillin reaction | journal = Journal of Allergy | volume = 30 | issue = 4 | pages = 337–41 | date = July 1959 | pmid = 13664435 | doi = 10.1016/0021-8707(59)90041-3 }}</ref><ref>{{Cite book | author = United States Congress Senate Committee on the Judiciary |url=https://books.google.com/books?id=dnMopURBpCgC&pg=PA3162|title=Drug Industry Antitrust Act: Hearings Before the Subcommittee on Antitrust and Monopoly of the Committee on the Judiciary, United States Senate, Eighty-seventh Congress, First [-second] Session, Pursuant to S. Res. 52 on S. 1552, a Bill to Amend and Supplement the Antitrust Laws, with Respect to the Manufacture and Distribution of Drugs, and for Other Purposes|date=1961|publisher=U.S. Government Printing Office|language=en}}</ref> The [[Albany Medical Center|Albany Hospital]] removed it from its formulary in 1960, only two years after adding it, citing lack of use.<ref>{{Cite book | author = United States Congress Senate Committee on the Judiciary Subcommittee on Antitrust and Monopoly |url=https://books.google.com/books?id=hYPQ_wIioMcC&pg=PA10601|title=Administered Prices: con't] pt.25. Administered prices in the drug industry, (Antibiotics-Appendix A). 1961. pp. 14201-15329|date=1957|publisher=U.S. Government Printing Office|language=en}}</ref> Some researchers continued to use it in experiments on penicillin resistance as late as 1972.<ref>{{cite journal | vauthors = Lindström EB, Nordström K | title = Automated method for determination of penicillins, cephalosporins, and penicillinases | journal = Antimicrobial Agents and Chemotherapy | volume = 1 | issue = 2 | pages = 100–6 | date = February 1972 | pmid = 4618452 | pmc = 444176 | doi = 10.1128/aac.1.2.100 }}</ref> It was voluntarily withdrawn from the American market by 3M Pharmaceuticals in 1997.<ref>{{Cite web|title=Federal Register, Volume 62 Issue 229 (Friday, November 28, 1997)|url=https://www.govinfo.gov/content/pkg/FR-1997-11-28/html/97-31214.htm|access-date=2020-12-24|website=www.govinfo.gov|archive-date=23 October 2023|archive-url=https://web.archive.org/web/20231023152633/https://www.govinfo.gov/content/pkg/FR-1997-11-28/html/97-31214.htm|url-status=live}}</ref>

== Detection ==

Beta-lactamase enzymatic activity can be detected using [[nitrocefin]], a chromogenic [[cephalosporin]] substrate which changes color from yellow to red upon beta-lactamase mediated hydrolysis.<ref name="pmid4208895">{{cite journal | vauthors = O'Callaghan CH, Morris A, Kirby SM, Shingler AH | title = Novel method for detection of beta-lactamases by using a chromogenic cephalosporin substrate | journal = Antimicrobial Agents and Chemotherapy | volume = 1 | issue = 4 | pages = 283–8 | date = April 1972 | pmid = 4208895 | pmc = 444209 | doi = 10.1128/AAC.1.4.283 }}</ref>

Extended spectrum beta lactamase (ESBL) screening can be performed using disk-diffusion. Cefpodoxime, ceftazidime, aztreonam, cefotaxime, and/or ceftriaxone discs are used.<ref>{{Cite journal |last1=Rawat |first1=Deepti |last2=Nair |first2=Deepthi |date=2010 |title=Extended-spectrum ß-lactamases in gram negative bacteria |journal=Journal of Global Infectious Diseases |language=en |volume=2 |issue=3 |pages=263–274 |doi=10.4103/0974-777X.68531 |doi-access=free |issn=0974-777X |pmc=2946684 |pmid=20927289}}</ref> 

==Evolution==
Beta-lactamases are ancient bacterial enzymes. Metallo β-lactamases ("class B") are all structurally similar to [[RNase Z]] and may have evolved from it. Of the three subclasses B1, B2, and B3, B1 and B2 are theorized to have evolved about one [[Bya|billion years ago]], while B3 seems to have arisen independently, possibly before the divergence of the gram-positive and gram-negative eubacteria about two billion years ago.<ref name=Hall2004>{{cite journal | vauthors = Hall BG, Salipante SJ, Barlow M | title = Independent origins of subgroup Bl + B2 and subgroup B3 metallo-beta-lactamases | journal = Journal of Molecular Evolution | volume = 59 | issue = 1 | pages = 133–41 | date = July 2004 | pmid = 15383916 | doi = 10.1007/s00239-003-2572-9 | bibcode = 2004JMolE..59..133H | s2cid = 30833168 }}</ref> PNGM-1 (Papua New Guinea Metallo-β-lactamase-1) has both metallo-β-lactamase (MBL) and tRNase Z activities, suggesting that PNGM-1 is thought to have evolved from a tRNase Z, and that the B3 MBL activity of PNGM-1 is a promiscuous activity and subclass B3 MBLs are thought to have evolved through PNGM-1 activity.<ref>{{cite journal | vauthors = Lee JH, Takahashi M, Jeon JH, Kang LW, Seki M, Park KS, Hong MK, Park YS, Kim TY, Karim AM, Lee JH, Nashimoto M, Lee SH | title = Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-''β''-lactamases: a molecular and evolutionary study | journal = Emerging Microbes & Infections | volume = 8 | issue = 1 | pages = 1688–1700 | year = 2019 | pmid = 31749408 | pmc = 6882493 | doi = 10.1080/22221751.2019.1692638 | doi-access = free }}</ref> Subclasses B1 and B3 has been further subdivided.<ref>{{cite journal | vauthors = Berglund F, Johnning A, Larsson DG, Kristiansson E | title = An updated phylogeny of the metallo-β-lactamases | journal = The Journal of Antimicrobial Chemotherapy | volume = 76 | issue = 1 | pages = 117–123 | date = January 2021 | pmid = 33005957 | doi = 10.1093/jac/dkaa392 }}</ref>

Serine beta-lactamases (classes A, C, and D) appear to have evolved from [[DD-Transpeptidase|<small>DD</small>-transpeptidase]]s, which are [[penicillin-binding protein]]s involved in cell wall biosynthesis, and as such are one of the main targets of beta-lactam antibiotics.<ref>{{InterPro|IPR012338}}</ref> These three classes show undetectable sequence similarity with each other, but can still be compared using structural homology. Groups A and D are sister taxa and group C diverged before A and D.<ref name=Hall2003>{{cite journal | vauthors = Hall BG, Barlow M | title = Structure-based phylogenies of the serine beta-lactamases | journal = Journal of Molecular Evolution | volume = 57 | issue = 3 | pages = 255–60 | date = September 2003 | pmid = 14629035 | doi = 10.1007/s00239-003-2473-y | s2cid = 187389 }}</ref> These serine-based enzymes, like the group B betalactamases, are of ancient origin and are theorized to have evolved about two billion years ago.<ref name="pmid15158767">{{cite journal | vauthors = Hall BG, Barlow M | title = Evolution of the serine beta-lactamases: past, present and future | journal = Drug Resistance Updates | volume = 7 | issue = 2 | pages = 111–23 | date = April 2004 | pmid = 15158767 | doi = 10.1016/j.drup.2004.02.003 }}</ref>

The OXA group (in class D) in particular is theorized to have evolved on chromosomes and moved to plasmids on at least two separate occasions.<ref name=Barlow2002>{{cite journal | vauthors = Barlow M, Hall BG | title = Phylogenetic analysis shows that the OXA beta-lactamase genes have been on plasmids for millions of years | journal = Journal of Molecular Evolution | volume = 55 | issue = 3 | pages = 314–21 | date = September 2002 | pmid = 12187384 | doi = 10.1007/s00239-002-2328-y | s2cid = 8679468 | bibcode = 2002JMolE..55..314B }}</ref>

==Etymology==
The "β" ([[beta]]) refers to the [[nitrogen]]'s [[locant#Greek letter locants|position]] on the second carbon in the ring. ''[[Lactam]]'' is a blend of ''[[lactone]]'' (from the [[Latin language|Latin]] ''lactis'', ''milk'', since [[lactic acid]] was isolated from soured milk) and ''[[amide]]''. The suffix ''[[-ase]]'', indicating an enzyme, is derived from ''[[diastase]]'' (from the [[Greek language|Greek]] ''diastasis'', "separation"), the first enzyme discovered in 1833 by Payen and Persoz.<ref>{{Cite journal |doi = 10.3201/eid2209.ET2209|title = Etymologia: β-Lactamase|journal = Emerging Infectious Diseases|year = 2016|volume = 22|issue = 9|pages = 1689–1631|doi-access = free|pmc = 4994330}}</ref>

== See also ==
* [[β-lactamase inhibitor]]
* [[Escherichia coli#Beta-lactamase strains|ESBL-producing ''E. coli'']]
* [[Nitrocefin]]
* [[Antimicrobial resistance]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Sawa T, Kooguchi K, Moriyama K | title = Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance | journal = Journal of Intensive Care | volume = 8 | issue = 1 | article-number = 13 | date = December 2020 | pmid = 32015881 | doi = 10.1186/s40560-020-0429-6 | pmc = 6988205 | doi-access = free }}
* {{cite journal | vauthors = Philippon A, Slama P, Dény P, Labia R | title = A Structure-Based Classification of Class A β-Lactamases, a Broadly Diverse Family of Enzymes | journal = Clinical Microbiology Reviews | volume = 29 | issue = 1 | pages = 29–57 | date = January 2016 | pmid = 26511485 | doi = 10.1128/CMR.00019-15 | pmc = 4771212 | doi-access = free }}
* {{cite journal | vauthors = Yoon EJ, Jeong SH | title = Class D β-lactamases | journal = The Journal of Antimicrobial Chemotherapy | volume = 76 | issue = 4 | pages = 836–864 | date = March 2021 | pmid = 33382875 | doi = 10.1093/jac/dkaa513 }}
{{refend}}

== External links ==
* [http://bldb.eu/ Beta-lactamase database]
* {{MeshName|beta-Lactamases}}

{{Carbon-nitrogen non-peptide hydrolases}}
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[[Category:Beta-lactam antibiotics]]
[[Category:EC 3.5.2]]
[[Category:Enzymes of known structure]]