Next-generation rifamycins for the treatment of mycobacterial infections
Abstract
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 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 M. abscessus 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 Mycobacterium tuberculosis , 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 M. abscessus 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 M. abscessus lung infection.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (29)
Véronique Dartois
Center for Discovery and Innovation, Hackensack Meridian Health
Tian Lan
Uday S. Ganapathy
Center for Discovery and Innovation, Hackensack Meridian Health
Chui Fann Wong
Center for Discovery and Innovation, Hackensack Meridian Health
Jickky P. Sarathy
Center for Discovery and Innovation, Hackensack Meridian Health
Diana C. Jimenez
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Ilham M. Alshiraihi
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Ha Lam
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Suyapa Rodriguez
Center for Discovery and Innovation, Hackensack Meridian Health
Min Xie
Maritza Soto-Ojeda
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Mary Jackson
William Wheat
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Nathan C. Dillman
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota
Kateryna Kostenkova
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota
Jake Schmitt
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota
Lea Mann
Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg
Adrian Richter
Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg
Peter Imming
Jansy Sarathy
Center for Discovery and Innovation, Hackensack Meridian Health
Firat Kaya
Center for Discovery and Innovation, Hackensack Meridian Health
Sindhuja Paruchuri
Center for Discovery and Innovation, Hackensack Meridian Health
Betelhem Tatek
Center for Discovery and Innovation, Hackensack Meridian Health
Camilla Folvar
Center for Discovery and Innovation, Hackensack Meridian Health
Julianna Proietto
Center for Discovery and Innovation, Hackensack Meridian Health
Matthew Zimmerman
Center for Discovery and Innovation, Hackensack Meridian Health
Mercedes Gonzalez-Juarrero
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University
Courtney C. Aldrich
Thomas Dick
Center for Discovery and Innovation, Hackensack Meridian Health