Next- generation rifamycins for the treatment of mycobacterial infections

• 成果类型: Article
• 署名作者: Dartois, Veronique; Lan, Tian; Ganapathy, Uday S.; Wong, Chui Fann; Sarathy, Jickky P.; Jimenez, Diana C.; Alshiraihi, Ilham M.; Lam, Ha; Rodriguez, Suyapa; Xie, Min; Soto-Ojeda, Maritza; Jackson, Mary; Wheat, William; Dillman, Nathan C.; Kostenkova, Kateryna; Schmitt, Jake; Mann, Lea; Richter, Adrian; Imming, Peter; Sarathy, Jansy; Kaya, Firat; Paruchuri, Sindhuja; Tatek, Betelhem; Folvar, Camilla; Proietto, Julianna; Zimmerman, Matthew; Gonzalez-Juarrero, Mercedes; Aldrich, Courtney C.; Dick, Thomas
• 署名单位: University of Minnesota System; University of Minnesota Twin Cities; Colorado State University System; Colorado State University Fort Collins; Martin Luther University Halle Wittenberg; Georgetown University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10124
• DOI: 10.1073/pnas.2423842122
• 发表日期: 2025-05-01
• 关键词: tuberculosis; rifapentine; resistance; rifabutin; moxifloxacin; mechanism; regimens; rifampin; agents

摘要

Mycobacterium abscessus is a rapidly growing nontuberculous Mycobacterium 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. abscessus lung disease is severely cytochrome P450 3A4 (CYP3A4), a major human drug- metabolizing enzyme, further limiting their use in patients with comorbidities that require treatment with CYP3A4 substrates such as CF and HIV coinfection. We chemically reengineered rifabutin to enhance its potency against M. abscessus by blocking intrabacterial inactivation and eliminate drug-drug interactions by removing induction of CYP3A4 gene expression. We lar inactivation and lacking CYP3A4 induction, while retaining excellent pharmacologthe frontrunners are equipotent to rifabutin, suggesting superior clinical utility since clinical isolates, were highly bactericidal against replicating and drug- tolerant nonrep