Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 SE Harvard St SE, Minneapolis, MN 55455, USA.
Center for Discovery and Innovation, Hackensack Meridian Health & Department of Medical Sciences, Hackensack Meridian School of Medicine, 123 Metro Boulevard, Nutley, NJ 07110, USA.
Angew Chem Int Ed Engl. 2022 Nov 7;61(45):e202211498. doi: 10.1002/anie.202211498. Epub 2022 Oct 12.
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.
利福霉素类抗生素是一类具有重要价值的抗菌药物，可用于治疗分枝杆菌和其他持续性细菌感染，这是由于它们对复制期和非复制期病原体具有强大的杀菌活性。然而，由于一种新的耐药机制，即 ADP-核糖基化导致利福霉素失活，利福霉素类药物在治疗脓肿分枝杆菌感染方面的临床应用受到严重限制。本研究采用基于结构的方法，通过对ansa 链进行策略性修饰，合理重新设计利福霉素，从而阻断 ADP-核糖基化，同时保留针对目标的活性。通过生化、结构和微生物学研究的组合验证，最有效的类似物能够克服 ADP-核糖基化，恢复其内在的低纳摩尔活性，并在体内显示出显著的抗菌功效。通过调整药物处置特性进一步优化，得到了一个具有显著效力和出色药代动力学特性的临床前候选药物。
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