Yohei Doi, MD, PhD, has been awarded funding in the amount of $420,250 for a two-year grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled “Mechanisms of cefiderocol resistance”. This proposal was submitted in response to the competitive funding opportunity entitled NIH Exploratory/Developmental Research Grant Program (Parent R21) under funding opportunity number PA-19-053.
Antimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern. Cefiderocol is a new catechol-substituted siderophore cephalosporin currently undergoing late-stage clinical development. It is actively transported across the Gramnegative outer membrane and is stable against all classes of beta-lactamases, resulting in potent activity across Gram-negative bacterial species. While rare cefiderocol-resistant strains have been reported in surveillance studies, the mechanisms underlying cefiderocol resistance are largely unknown.
With its unparalleled spectrum of activity across Gram-negative species, cefiderocol is likely to become a crucially important agent in the treatment of carbapenem-resistant Gram-negative infections, but information regarding the mechanisms of resistance and the risk of their emergence is non-existent. This project will address key questions to optimize use of cefiderocol in the clinic and insights into the structure-activity relationship of substrate-binding sites of cefiderocolhydrolyzing beta-lactamases will inform designing of the next-generation cephalosporins.