Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance.
Angew Chem Int Ed Engl
; 61(45): e202211498, 2022 11 07.
Article
em En
| MEDLINE
| ID: mdl-36222275
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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Base de dados:
MEDLINE
Assunto principal:
Rifamicinas
/
Mycobacterium
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article