Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases

Pemberton, Orville A.; Zhang, Xiujun; Nichols, Derek A.; DeFrees, Kyle; Jaishankar, Priyadarshini; Bonnet, Richard; Adams, Jessie; Shaw, Lindsey N.; Renslo, Adam R.; Chen, Yu

doi:10.1128/AAC.02563-17

Title: Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases

Journal Article · Tue May 29 00:00:00 EDT 2018 · Antimicrobial Agents and Chemotherapy

DOI:https://doi.org/10.1128/AAC.02563-17· OSTI ID:1504986

Pemberton, Orville A.; Zhang, Xiujun; Nichols, Derek A.; DeFrees, Kyle; Jaishankar, Priyadarshini; Bonnet, Richard; Adams, Jessie;

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ABSTRACT CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived noncovalent inhibitor of CTX-M-9. Here, we present the biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while it exhibited some low-level inhibition of other serine β-lactamases. Complex crystal structures with the CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active-site residues on the β3 strand.In vitropharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine β-lactamase inhibitor discovery.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1504986

Journal Information:: Antimicrobial Agents and Chemotherapy, Vol. 62, Issue 8; ISSN 0066-4804

Publisher:: American Society for Microbiology

Country of Publication:: United States

Language:: ENGLISH

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