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

Overview

Journal Angew Chem Int Ed Engl

Specialty Chemistry

Date 2022 Oct 12

PMID 36222275

Authors

Tian Lan

Uday S Ganapathy

Sachin Sharma

Yong-Mo Ahn

Matthew Zimmerman

Vadim Molodtsov

Pooja Hegde

Martin Gengenbacher

Richard H Ebright

Veronique Dartois

Joel S Freundlich

Thomas Dick

Courtney C Aldrich

Affiliations

Soon will be listed here.

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.

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