Beta-lactamase
Serine beta-lactamase | |||||||||||
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Metallo-beta-lactamase | |||||||||
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Identifiers | |||||||||
Symbol | ? | ||||||||
Pfam | PF00753 | ||||||||
Pfam clan | CL0381 | ||||||||
InterPro | IPR001279 | ||||||||
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β-lactamase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Beta-lactamases (β-lactamases) are
Beta-lactamases produced by Gram-negative bacteria are usually secreted, especially when antibiotics are present in the environment.[1]
Structure
The structure of a Streptomyces serine β-lactamase (SBLs) is given by 1BSG. The alpha-beta fold (InterPro: IPR012338) resembles that of a DD-transpeptidase, from which the enzyme is thought to have evolved. β-lactam antibiotics bind to DD-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 Zn2+ ions
Mechanism of action
The two types of beta-lactamases work on the basis of the two basic mechanisms of opening the β-lactam ring.[2]
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]
The MBLs use the Zn2+ 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.[4]
Penicillinase
Penicillinase is a specific type of β-lactamase, showing specificity for
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,
Resistance in Gram-negative bacteria
This section may require cleanup to meet Wikipedia's quality standards. The specific problem is: confusing mix of structural and functional classifications; need explanatory paragraph on what these classes are. (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 (
Extended-spectrum beta-lactamase (ESBL)
Members of this family commonly express β-lactamases (e.g., TEM-3, TEM-4,[7] and SHV-2 [8]) 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).[9] The prevalence of ESBL-producing bacteria have been gradually increasing in acute care hospitals.[10] The prevalence in the general population varies between countries, e.g. approximately 6% in Germany[11] and France,[12] 13% in Saudi Arabia,[13] and 63% in Egypt.[14] 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 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.[15] 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. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant (primarily ertapenem-resistant) isolates have recently been reported.[16] ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates.[citation needed]
Types
TEM beta-lactamases (class A)
TEM-1 is the most commonly encountered beta-lactamase in
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
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[23] 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.[24] An example of beta-lactamase CTX-M-15, along with ISEcp1, has been found to have transposed onto the chromosome of Klebsiella pneumoniae ATCC BAA-2146.[25] The initials stand for "Cefotaxime-Munich".[26]
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
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
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
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
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 .
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.[29]
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 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.[30]
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[update], the class A Klebsiella pneumoniae carbapenemase (KPC) globally has been the most common carbapenemase, and was first detected in 1996 in North Carolina, USA.[31] A 2010 publication indicated that KPC producing Enterobacteriaceae were becoming common in the United States.[32]
CMY (class C)
The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes.[33] It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.[34]
SME (Serratia marcescens enzymes), IMI (IMIpenem-hydrolysing β-lactamase), NMC and CcrA
In general, these are of little clinical significance.
CcrA (CfiA). Its gene occurs in ca. 1–3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent increase.
NDM-1 (New Delhi metallo-β-lactamase) (class B)
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.[35] NDM have several variants which share different properties.[29]
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
According to genes
ESBLs
Strains producing only ESBLs are susceptible to
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 105 to 107 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
AmpC
AmpC-producing strains are typically resistant to
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
According to species
Escherichia coli or Klebsiella
For infections caused by ESBL-producing
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.
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.[46]
Extended spectrum beta lactamase (ESBL) screening can be performed using disk-diffusion. Cefpodoxime, ceftazidime, aztreonam, cefotaxime, and/or ceftriaxone discs are used.[47]
Evolution
Beta-lactamases are ancient bacterial enzymes. Metallo β-lactamases ("class B") are all structurally similar to
Serine beta-lactamases (classes A, C, and D) appear to have evolved from
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.[54]
Etymology
The "β" (
See also
- β-lactamase inhibitor
- ESBL-producing E. coli
- Nitrocefin
References
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Further reading
- Sawa T, Kooguchi K, Moriyama K (December 2020). "Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance". Journal of Intensive Care. 8 (1): 13. PMID 32015881.
- Philippon A, Slama P, Dény P, Labia R (January 2016). "A Structure-Based Classification of Class A β-Lactamases, a Broadly Diverse Family of Enzymes". Clinical Microbiology Reviews. 29 (1): 29–57. PMID 26511485.
- Yoon EJ, Jeong SH (March 2021). "Class D β-lactamases". The Journal of Antimicrobial Chemotherapy. 76 (4): 836–864. PMID 33382875.
External links
- Beta-lactamase database
- beta-Lactamases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)