Angewandte Chemie (International ed. in English) · 2022
Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Lan Tian, Ganapathy Uday S, Sharma Sachin, Ahn Yong-Mo, Zimmerman Matthew, Molodtsov Vadim, Hegde Pooja, Gengenbacher Martin, Ebright Richard H, Dartois Véronique, Freundlich Joel S, Dick Thomas, Aldrich Courtney C
Аннотация
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.