ArticleProceedings of the National Academy of Sciences of the United States of America2016
Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 142 citations in OpenAlex.
- Phenotypic and biochemical characterization of the class C β-lactamase, PAC-1.The Journal of antimicrobial chemotherapy · 2026Article
- Structural and functional characterization of an active site-influencing variant (IMP-1-F218Y) in IMP-1 metallo-β-lactamase.The FEBS journal · 2026Article
- Phenotypic and genotypic characterization of HMB-3, a metallo-beta-lactamase from Pseudomonas asiatica.The Journal of antimicrobial chemotherapy · 2026Article
- Inhibitor Affinity Differs among Clinical Variants of IMP Metallo-ACS infectious diseases · 2025Article
- Active site loops of membrane-anchored metallo-β-lactamases from environmental bacteria determine cephalosporinase activity.Antimicrobial agents and chemotherapy · 2025Article
- Small-molecule strategies to combat antibiotic resistance: mechanisms, modifications, and contemporary approaches.RSC advances · 2025Review
- Spectrum of cefepime-taniborbactam coverage against 190 β-lactamases defined in engineered isogenicAntimicrobial agents and chemotherapy · 2025Article
- Novel enantiopure δ-thiolactones: synthesis, structural characterization, and reactivity studies.RSC advances · 2024Article
- Elucidation of critical chemical moieties of metallo-β-lactamase inhibitors and prioritisation of target metallo-β-lactamases.Journal of enzyme inhibition and medicinal chemistry · 2024Review
- Role of β-Lactamase Inhibitors as Potentiators in Antimicrobial Chemotherapy Targeting Gram-Negative Bacteria.Antibiotics (Basel, Switzerland) · 2024Review
- Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes.Journal of medicinal chemistry · 2024Article
- Structural role of K224 in taniborbactam inhibition of NDM-1.Antimicrobial agents and chemotherapy · 2024Article
- Identification of isothiazolones analogues as potent bactericidal agents against antibiotic resistant CRE and MRSA strains.BMC chemistry · 2023Article
- In-cell kinetic stability is an essential trait in metallo-β-lactamase evolution.Nature chemical biology · 2023Article
- Review
- Review
- Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase.eLife · 2023Article
- Structural insights into the substrate specificity of IMP-6 and IMP-1 metallo-β-lactamases.Journal of biochemistry · 2022Article
- A Cephalosporin-Tripodalamine Conjugate Inhibits Metallo-β-Lactamase with High Efficacy and Low Toxicity.Antimicrobial agents and chemotherapy · 2022Article
- Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition.Molecules (Basel, Switzerland) · 2022Review
11 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 6 institutions in 4 countries.
Funding
Abstract
Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both l- and d-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Kis of 6-15 µM or 36-84 µM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 µM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the l-BTZ enantiomers exhibit 100-fold lower Kis (0.26-0.36 µM) than d-BTZs (26-29 µM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the l-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. d-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding.
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