Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance. Issue 45 (12th October 2022) - Lan, Tian
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 and non‐replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP‐ribosylation. Using a structure‐based approach, we rationally redesign rifamycins through strategic modification of the ansa ‐chain to block ADP‐ribosylation while preserving on‐target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP‐ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile. Abstract : The first antibiotics with low nanomolar activity against the multidrug‐resistant Mycobacterium abscessus are achieved by rational redesign of rifamycins. Structure‐based modification on the rifamycin ansa ‐chain, together with microbiological, biochemical, biophysical and in vivo characterizations, provides novel candidates that are 300‐fold more active than rifampicin, completely bypass the resistance, and possess promising pharmacokinetic profiles.