Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance

Abstract Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating non‐replicating pathogens. However, the clinical utility rifamycins Mycobacterium abscessus is seriously compromised novel resistance mechanism, namely, rifamycin inactivation ADP‐ribosylation. Using structure‐based approach, we rationally redesign through strategic modification ansa ‐chain block ADP‐ribosylation while preserving on‐target activity. Validated combination biochemical, structural, microbiological studies, most analogs overcome ADP‐ribosylation, restored intrinsic low nanomolar demonstrated significant in vivo antibacterial efficacy. Further optimization tuning drug disposition properties afforded preclinical candidate with remarkable potency an outstanding pharmacokinetic profile.