Next-generation rifamycins for the treatment of mycobacterial infections

<i>Mycobacterium abscessus</i> is a rapidly growing nontuberculous <i>Mycobacterium</i> 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 <i>M. abscessus</i> lung disease is severely compromised by intrabacterial ADP-ribosylation. Additionally, rifamycins induce 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 <i>M. abscessus</i> by blocking intrabacterial inactivation and eliminate drug-drug interactions by removing induction of CYP3A4 gene expression. We have designed and profiled a series of C25-substituted derivatives resistant to intracellular inactivation and lacking CYP3A4 induction, while retaining excellent pharmacological properties. Against <i>Mycobacterium tuberculosis</i>, devoid of ADP-ribosyltransferase, the frontrunners are equipotent to rifabutin, suggesting superior clinical utility since they no longer come with the drug interaction liability typical of rifamycins. Prioritized compounds demonstrated superior antibacterial activity against a panel of <i>M. abscessus</i> clinical isolates, were highly bactericidal against replicating and drug-tolerant nonreplicating bacteria in caseum surrogate and were active against intracellular bacteria. As single agents, these rifamycins were as effective as a standard-of-care four-drug combination in a murine model of <i>M. abscessus</i> lung infection.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-01
DOI
https://doi.org/10.1073/pnas.2423842122
Citations
9
Primary Topic
Mycobacterium research and diagnosis
Type
article
Field-Weighted Citation Impact
12.19

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article

Next-generation rifamycins for the treatment of mycobacterial infections

Sergio D. Rodríguez, Lea Mann, Véronique Dartois, Jickky Palmae Sarathy et al.
9 citations
Proceedings of the National Academy of Sciences
Mycobacterium research and diagnosis
12.19
article

Next-generation rifamycins for the treatment of mycobacterial infections

Sergio D. Rodríguez, Lea Mann, Véronique Dartois, Jickky Palmae Sarathy, Chui Fann Wong, Firat Kaya, Judith Schmitt, Diana C. Jimenez, Ilham Alshiraihi, Courtney C. Aldrich, Peter Imming, Uday S. Ganapathy, William H. Wheat, Mary Jackson, Adrian Richter, Matthew Zimmerman, Kateryna Kostenkova, Jansy P. Sarathy, H. Lam, Thomas Dick, Mercedes Gonzalez‐Juarrero, Maritza Soto-Ojeda, Tian Lan, Min Xie, Sindhuja Paruchuri, Julianna Proietto, Betelhem Tatek, Camilla Folvar, Nathan C. Dillman
article en
9 citations

Abstract

<i>Mycobacterium abscessus</i> is a rapidly growing nontuberculous <i>Mycobacterium</i> 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 <i>M. abscessus</i> lung disease is severely compromised by intrabacterial ADP-ribosylation. Additionally, rifamycins induce 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 <i>M. abscessus</i> by blocking intrabacterial inactivation and eliminate drug-drug interactions by removing induction of CYP3A4 gene expression. We have designed and profiled a series of C25-substituted derivatives resistant to intracellular inactivation and lacking CYP3A4 induction, while retaining excellent pharmacological properties. Against <i>Mycobacterium tuberculosis</i>, devoid of ADP-ribosyltransferase, the frontrunners are equipotent to rifabutin, suggesting superior clinical utility since they no longer come with the drug interaction liability typical of rifamycins. Prioritized compounds demonstrated superior antibacterial activity against a panel of <i>M. abscessus</i> clinical isolates, were highly bactericidal against replicating and drug-tolerant nonreplicating bacteria in caseum surrogate and were active against intracellular bacteria. As single agents, these rifamycins were as effective as a standard-of-care four-drug combination in a murine model of <i>M. abscessus</i> lung infection.

Proceedings of the National Academy of SciencesVol. 122(18)
University of Minnesota (US), Georgetown University (US), Hackensack Meridian Health (US), Center for Discovery (US), Martin Luther University Halle-Wittenberg (DE), Colorado State University (US)
Deutsche Forschungsgemeinschaft, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 1%
Mycobacterium research and diagnosis
12.19
DOIOpen Access PDFOpenAlex
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