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Cited by 1,709Antibiotic Resistance in BacteriaAntibiotics Pharmacokinetics and EfficacySynthesis of β-Lactam Compounds

Three Decades of β-Lactamase Inhibitors

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Drawz, Sarah M., Bonomo, Robert A.·2010·Clinical Microbiology Reviews
DOI 10.1128/cmr.00037-09PMC PMC2806661
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Abstract

Since the introduction of penicillin, beta-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial beta-lactamases. beta-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome beta-lactamase-mediated resistance, beta-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner beta-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to beta-lactam-beta-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant beta-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of beta-lactams. Here, we review the catalytic mechanisms of each beta-lactamase class. We then discuss approaches for circumventing beta-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of beta-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a "second generation" of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of beta-lactamases.

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  • Clavulanic acid binds irreversibly to the active site of β-lactamase enzymes, protecting amoxicillin from enzymatic degradation and restoring its antimicrobial spectrum.

    “Clavulanic acid, a potent β-lactamase inhibitor, was developed to overcome this limitation by binding irreversibly to the active site of β-lactamase enzymes, thereby protecting amoxicillin from enzymatic degradation and restoring its antimicrobial spectrum [3].”

    From Clinical Outcomes and Real-World Effectiveness of Amoxicillin-Clavulanic Acid Across Indian Healthcare Settings: A Retrospective Multicenter Study (2026) · cites this paper as [3]

    The Introduction says clavulanate inhibits β-lactamases and significantly expands amoxicillin’s spectrum against several penicillinase-producing bacteria. Its mechanism discussion, however, says inhibition can end in either irreversible inactivation or deacylation that regenerates active β-lactamase. The claim overstates irreversible binding as the outcome for β-lactamase enzymes generally. (LLM, conf=0.88)

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Authors
Drawz, S. M., & Bonomo, R. A.
Affiliations
  • Departments of Pathology
  • United States Department of Veterans Affairs (US)
Corresponding author
Bonomo, Robert A.
ORCID
Bonomo, Robert A.
Venue
Clinical Microbiology Reviews
Publisher
American Society for Microbiology
Published
2010-01
Volume
23
Issue
1
Pages
160-201
ISSN
  • 0893-8512 (ISSN-L)
  • 1098-6618
DOI
10.1128/cmr.00037-09
PMC
PMC2806661
OpenAlex
W1895007034
Cited by
1,709
References
464
Citations by year
2026: 83 · 2025: 100 · 2024: 87 · 2023: 86 · 2022: 106 · 2021: 126 · 2020: 151 · 2019: 130 · 2018: 131 · 2017: 119 · 2016: 120 · 2015: 108 · 2014: 93 · 2013: 88 · 2012: 81
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Clinical Microbiology Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service (1R01A1063517-01)
  • National Institute of General Medical Sciences (T32GM007250, T32GM07250)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis of β-Lactam Compounds
Keywords
beta-lactamase inhibitors, beta-lactamase, beta-lactam resistance, clavulanic acid, sulbactam, tazobactam, mechanism-based inactivators, carbapenemase inhibitors, extended-spectrum cephalosporin resistance, Enterobacteriaceae, penicillin-resistant staphylococci
MeSH terms
Bacteria, Bacterial Infections, Bacterial Proteins, beta-Lactamases, Enzyme Inhibitors, Humans, beta-Lactam Resistance, beta-Lactamase Inhibitors

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