Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185
Akito Kawai, William C. Shropshire, Masahiro Suzuki, Jovan Borjan, Samuel L Aitken, William C. Bachman, Christi L. McElheny, Micah M. Bhatti, Ryan K. Shields, Samuel A. Shelburne, Yohei Doi
Abstract
including strains with or without production of serine carbapenemases. After its launch, emergence of ceftazidime-avibactam-resistant strains that produce mutated β-lactamases capable of efficiently hydrolyzing ceftazidime or impairing avibactam inhibition are increasingly reported. Furthermore, cross-resistance towards cefiderocol, the latest cephalosporin in clinical use, has been observed in some instances. Here, we clearly demonstrate the functional role of the substituted residues in CMY-185, a four amino-acid variant of CMY-2 identified in a patient treated with ceftazidime-avibactam, for high-level resistance to this agent and low-level resistance to cefiderocol. These findings provide structural insights into how β-lactamases may incrementally alter their structures to escape multiple advanced β-lactam agents.