6BT6

CTX-M-14 S237A Beta-Lactamase in Complex with a Non-Covalent Tetrazole Inhibitor

Summary for 6BT6

• Entry DOI: 10.2210/pdb6bt6/pdb
• Descriptor: Beta-lactamase, N-[3-(2H-tetrazol-5-yl)phenyl]-6-(trifluoromethyl)-1H-benzimidazole-4-carboxamide (3 entities in total)
• Functional Keywords: tetrazole, inhibitor, beta-lactamase, esbl, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 57428.20

Authors

Pemberton, O.A.,Chen, Y. (deposition date: 2017-12-05, release date: 2018-06-13, Last modification date: 2024-10-09)

Primary citation

Pemberton, O.A.,Zhang, X.,Nichols, D.A.,DeFrees, K.,Jaishankar, P.,Bonnet, R.,Adams, J.,Shaw, L.N.,Renslo, A.R.,Chen, Y.
Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine beta-Lactamases.
Antimicrob. Agents Chemother., 62:-, 2018

PubMed 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. pharmacokinetic 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.

PubMed: 29844038
DOI: 10.1128/AAC.02563-17

Experimental method

X-RAY DIFFRACTION (1.05 Å)