CDI: Next-Generation Rifamycins for Mycobacterial Infections

Mycobacterium abscessus is a rapidly growing non-tuberculous Mycobacterium causing severe pulmonary infections, especially in immunocompromised individuals and those with underlying lung conditions like cystic fibrosis.  M. abscessus pulmonary disease is a growing global health crisis due to limited therapeutic options and emerging drug-resistant strains.  Current treatments for the disease are severely limited.  Thomas Dick and Véronique Dartois from the Center for Discovery & Innovation, Nutley, NJ, led a collaborative team from multiple institutions that designed, synthesized, and performed preclinical evaluation of a new generation of rifamycin antibiotics.  The reengineered rifabutin analogs are specifically developed to overcome the intrinsic resistance of Mycobacterium abscessus to current rifamycins, which is primarily mediated by enzymatic ADP-ribosylation. Crucially, these new compounds also aim to eliminate or significantly reduce the problematic drug-drug interactions caused by the induction of the human drug-metabolizing enzyme CYP3A4, a major limitation of current rifamycin therapy, particularly in patients with comorbidities like cystic fibrosis and HIV coinfection.  The novel rifabutin analogs, UMN-120 and UMN-121, show significant promise as preclinical development candidates for treating Mycobacterium abscessus lung disease.  Advancing the preclinical candidates to investigational new drug enabling studies will not be easy.  It will require overcoming several scientific, technical, regulatory, and logistical obstacles: manufacturing the compounds at scale for the studies, conducting robust pharmacodynamics and mechanism-of-action studies, conducting acute and chronic toxicology studies, and more.  Preclinical programs are both costly and time-consuming, and funding gaps can significantly hinder progress. However, Thomas Dick and Véronique Dartois have dedicated over a decade to developing these candidates and remain fully committed to advancing them across the finish line.

AAAS EurekAlert News Release: https://www.eurekalert.org/news-releases/1082495

Dartois V, Lan T, Ganapathy US, Wong CF, Sarathy JP, Jimenez DC, Alshiraihi IM, Lam H, Rodriguez S, Xie M, Soto-Ojeda M, Jackson M, Wheat W, Dillman NC, Kostenkova K, Schmitt J, Mann L, Richter A, Imming P, Sarathy J, Kaya F, Paruchuri S, Tatek B, Folvar C, Proietto J, Zimmerman M, Gonzalez-Juarrero M, Aldrich CC, Dick T. Next-generation rifamycins for the treatment of mycobacterial infections. Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2423842122. doi: 10.1073/pnas.2423842122. Epub 2025 May 1. PMID: 40310456.

https://www.pnas.org/doi/10.1073/pnas.2423842122