Next-generation rifamycins for the treatment of mycobacterial infections

• DOI: 10.1073/pnas.2423842122
• Publication Date: 2025-05-01T14:49:28Z
• Authors: Véronique Dartois; Tian Lan; Uday S. Ganapathy; Chui Fann Wong; Jickky P. Sarathy; Diana C. Jimenez; Ilham M. Alshiraihi; Ha Lam; Suyapa Rodriguez; Min Xie; Maritza Soto-Ojeda; Mary Jackson; William Wheat; Nathan C. Dillman; Kateryna Kostenkova; Jake Schmitt; Lea Mann; Adrian Richter; Peter Imming; Jansy Sarathy; Firat Kaya; Sindhuja Paruchuri; Betelhem Tatek; Camilla Folvar; Julianna Proietto; Matthew Zimmerman; Mercedes Gonzalez...; Courtney C. Aldrich; Thomas Dick

Mycobacterium abscessus is a rapidly growing nontuberculous causing severe pulmonary infections, especially in immunocompromised individuals and patients with underlying lung conditions like cystic fibrosis (CF). While rifamycins are the pillar of tuberculosis treatment, their efficacy against M. disease severely compromised by intrabacterial ADP-ribosylation. Additionally, induce cytochrome P450 3A4 (CYP3A4), major human drug-metabolizing enzyme, further limiting use comorbidities that require treatment CYP3A4 substrates such as CF HIV coinfection. We chemically reengineered rifabutin to enhance its potency blocking inactivation eliminate drug-drug interactions removing induction gene expression. have designed profiled series C25-substituted derivatives resistant intracellular lacking induction, while retaining excellent pharmacological properties. Against tuberculosis, devoid ADP-ribosyltransferase, frontrunners equipotent rifabutin, suggesting superior clinical utility since they no longer come drug interaction liability typical rifamycins. Prioritized compounds demonstrated antibacterial activity panel isolates, were highly bactericidal replicating drug-tolerant nonreplicating bacteria caseum surrogate active bacteria. As single agents, these effective standard-of-care four-drug combination murine model infection.