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Review
. 2018 Sep 24;62(10):e01076-18.
doi: 10.1128/AAC.01076-18. Print 2018 Oct.

Past and Present Perspectives on β-Lactamases

Karen Bush  1
Affiliations
Review

Past and Present Perspectives on β-Lactamases

Karen Bush. Antimicrob Agents Chemother. .

Abstract

β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years ago. These well-studied enzymes, currently numbering almost 2,800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active-site serine. Metallo-β-lactamases also exist, with one or two catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently approved cephalosporins, monobactams, and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C, and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole-genome sequencing studies. Often, these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.

Keywords: ESBL; MBL; carbapenemase; cephalosporinase; penicillinase; β-lactam; β-lactamase.

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Figures

FIG 1
FIG 1
Molecular and functional relationships among β-lactamases (adapted from references and with permission). AV, avibactam; CA, clavulanic acid; Cb, carbapenem; Cp, cephalosporin; E, expanded-spectrum cephalosporin; M, monobactam; P, penicillin.
FIG 2
FIG 2
General reaction mechanism for binding of a β-lactam substrate (S) to a PBP (E) or a serine β-lactamase (E). Reversible formation of a Michaelis complex (E · S) which proceeds to a stable acyl enzyme (E—S) caused by reaction with the active-site serine. Hydrolysis occurs to form the microbiologically inactive ring-opened β-lactam (P) and either enzymatically active PBP (slow hydrolysis of acyl enzyme) or β-lactamase (Bla, high hydrolysis rate).
FIG 3
FIG 3
Increase in numbers of unique, naturally occurring β-lactamases (some data from reference as well as from http://www.lahey.org/Studies/ and https://www.ncbi.nlm.nih.gov/bioproject/PRJNA313047). (A) β-Lactamases enumerated according to molecular classes A, B, C, and D, with the total number of enzymes (all) equal to 2,771. (B) β-Lactamases enumerated according to major functional groups with their trivial names, AmpC, group 1; ESBLs, group 2be; and carbapenemases, groups 2f and 3.
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References

    1. Abraham EP, Chain E. 1940. An enzyme from bacteria able to destroy penicillin. Nature 146:837. doi:10.1038/146837a0. - DOI - PubMed
    1. Kirby WMN. 1944. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science 99:452–453. doi:10.1126/science.99.2579.452. - DOI - PubMed
    1. Fisher JF, Knowles JR. 1978. Bacterial resistance to β-lactams: the β-lactamases. Ann Rep Med Chem 13:239–248. doi:10.1016/S0065-7743(08)60628-4. - DOI
    1. Bush K, Bradford PA. 2016. β-Lactams and β-lactamase inhibitors: an overview, p 23–44. In Silver LL, Bush K (ed), Antibiotics and antibiotic resistance. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. - PMC - PubMed
    1. Bradford PA. 2001. Extended-spectrum β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 14:933–951. doi:10.1128/CMR.14.4.933-951.2001. - DOI - PMC - PubMed

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