beta-lactamase beta-lactamase beta-lactamases, (β-lactamases) are enzymes (ec 3.5.2.6) produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. beta-lactamase provides antibiotic resistance by breaking the antibiotics' 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. serine beta-lactamasestructure of streptomyces albus beta-lactamaseidentifierssymbolβ-lactamase domainpfampf00144pfam clancl0013interproipr001466prositeps00146scop256601 / scope / supfamavailable protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summarypdb1axb​, 1blp​, 1bsg​, 1bue​, 1e25​, 1ghi​, 1i2s​, 1n9b​, 1ong​, 2cc1​, 2gdn​, 3dwz​ metallo-beta-lactamasemetallo-beta-lactamase l1 homotetramer, stenotrophomonasidentifierssymbol?pfampf00753pfam clancl0381interproipr001279available protein structures:pfam structures / ecod pdbrcsb pdb; pdbe; pdbjpdbsumstructure summary β-lactamaseaction of β-lactamase and decarboxylation of the intermediateidentifiersec no.3.5.2.6cas no.9073-60-3 databasesintenzintenz viewbrendabrenda entryexpasynicezyme viewkeggkegg entrymetacycmetabolic pathwaypriamprofilepdb structuresrcsb pdb pdbe pdbsumgene ontologyamigo / quickgosearchpmcarticlespubmedarticlesncbiproteins core structure of penicillins (top) and cephalosporins (bottom). beta-lactam ring in red. 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-lactam antibiotics are typically used to target a broad spectrum of gram-positive and gram-negative bacteria. beta-lactamases produced by gram-negative bacteria are usually secreted, especially when antibiotics are present in the environment. 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 from. 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) on their active site for their catalytic activities. the structure of the new delhi metallo-beta-lactamase 1 is given by 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. 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. the mbls use the zn2+ ions to activate a binding site water molecule for the hydrolysis of the β-lactam ring. penicillinase penicillinase is a specific type of β-lactamase, showing specificity for penicillins, again by 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 gram-negative e. coli even before penicillin entered clinical use, 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 resistance to even these. resistance in gram-negative bacteria 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 (e. cloacae, 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., 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. extended-spectrum beta-lactamase (esbl) members of this family commonly express β-lactamases (e.g., tem-3, tem-4, and shv-2 ) 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). the prevalence of esbl-producing bacteria have been gradually increasing in acute care hospitals. the prevalence in the general population varies between countries, e.g. approximately 6% in germany and france, 13% in saudi arabia, and 63% in egypt. 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. 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. esbl-producing organisms may appear susceptible to some extended-spectrum cephalosporins. however, treatment with such antibiotics has been associated with high failure rates. 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 e. coli is due to the production of tem-1. 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 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) 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. the term tem comes from the name of the athenian patient (temoniera) from which the isolate was recovered in 1963. 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. the initials stand for "sulfhydryl reagent variable". 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 ctx-m enzymes are currently known. despite their name, a few are more active on ceftazidime than cefotaxime. they have mainly been found in strains of salmonella enterica serovar typhimurium and e. coli, but have also been described in other species of enterobacteriaceae and are the predominant esbl type in parts of south america. (they are also seen in eastern europe) ctx-m-14, ctx-m-3, and ctx-m-2 are the most widespread. ctx-m-15 is currently (2006) the most widespread type in e. coli the uk and is widely prevalent in the community. an example of beta-lactamase ctx-m-15, along with isecp1, has been found to have recently transposed onto the chromosome of klebsiella pneumoniae atcc baa-2146. the initials stand for "cefotaxime-munich". 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 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 e. coli are a cause of community-acquired urinary infections in the uk, and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamides. 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 e. coli, but also some strains of k. pneumoniae, klebsiella oxytoca, 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, 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. 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 inducible; it