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Article Dans Une Revue Antimicrobial Agents and Chemotherapy Année : 2018

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

Orville Pemberton
  • Fonction : Auteur
Xiujun Zhang
  • Fonction : Auteur
Derek Nichols
  • Fonction : Auteur
Kyle Defrees
  • Fonction : Auteur
Priyadarshini Jaishankar
  • Fonction : Auteur
Adam Adams
  • Fonction : Auteur
Lindsey Shaw
  • Fonction : Auteur
Adam Renslo
  • Fonction : Auteur
Yu Chen
  • Fonction : Auteur
Jessie Adams
  • Fonction : Auteur

Résumé

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 vitro 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.

Dates et versions

hal-02064661 , version 1 (12-03-2019)

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Citer

Orville Pemberton, Xiujun Zhang, Derek Nichols, Kyle Defrees, Priyadarshini Jaishankar, et al.. Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases. Antimicrobial Agents and Chemotherapy, 2018, 62 (8), ⟨10.1128/AAC.02563-17⟩. ⟨hal-02064661⟩
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