Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus
- JUAN MANUEL BELARDINELLI1
- DEEPSHIKHA VERMA1
- Wei Li1
- Charlotte Avanzi1
- CRYSTAL J. WIERSMA1
- JOHN T. WILLIAMS2
- BENJAMIN K. JOHNSON3
- MATTHEW ZIMMERMAN4
- NICHOLAS WHITTEL1
- BHANUPRIYA ANGALA1
- HAN WANG4
- VICTORIA JONES1
- VÉRONIQUE DARTOIS4
- VINICIUS C. N. DE MOURA1
- MERCEDES GONZALEZ-JUARRERO1
- Camron Pearce1
- ALAN R. SCHENKEL5
- KENNETH C. MALCOLM6
- JERRY A. NICK6
- SUSAN A. CHARMAN7
- TIMOTHY N. C. WELLS8
- BRENDAN K. PODELL1
- JONATHAN L. VENNERSTROM9
- DIANE J. ORDWAY1
- ROBERT B. ABRAMOVITCH2
- MARY JACKSON1
- 1. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
- 2. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
- 3. Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
- 4. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
- 5. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
- 6. Department of Medicine, National Jewish Health, Denver, CO, USA. Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
- 7. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
- 8. Medicines for Malaria Venture, Geneva, Switzerland.
- 9. College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Description
MATTHEW ZIMMERMAN HTTPS://ORCID.ORG/0000-0002-4390-3555NICHOLAS WHITTELBHANUPRIYA ANGALA HAN WANGVICTORIA JONESVÉRONIQUE DARTOIS HTTPS://ORCID.ORG/0000-0001-9470-5009VINICIUS C. N. DE MOURAMERCEDES GONZALEZ-JUARREROCAMRON PEARCE HTTPS://ORCID.ORG/0000-0002-5091-0331ALAN R. SCHENKEL HTTPS://ORCID.ORG/0000-0002-1603-5713KENNETH C. MALCOLMJERRY A. NICK HTTPS://ORCID.ORG/0000-0002-8910-3449SUSAN A. CHARMAN HTTPS://ORCID.ORG/0000-0003-1753-8213TIMOTHY N. C. WELLS HTTPS://ORCID.ORG/0000-0001-9796-847XBRENDAN K. PODELL HTTPS://ORCID.ORG/0000-0003-2548-8826JONATHAN L. VENNERSTROM HTTPS://ORCID.ORG/0000-0003-0075-2336DIANE J. ORDWAY HTTPS://ORCID.ORG/0000-0003-0003-326XROBERT B. ABRAMOVITCH HTTPS://ORCID.ORG/0000-0002-4119-4169AND MARY JACKSON
Abstract: Nontuberculous mycobacteria, including Mycobacterium abscessus, are important human pathogens that affect patients with structural lung disease and have limited treatment options. Belardinelli et al. show that genetic disruption of the two-component regulator dosRS in M. abscessus renders bacteria less able to adapt to hypoxic conditions and reduces tolerance to antibiotics. They identified three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, that can target DosRS and have similar phenotypic effects as genetic disruption. Mice chronically infected with M. abscessus and treated with OZ439 showed bactericidal responses comparable to treatment with standard-of-care antibiotics, and OZ439 potentiated the activity of some antibiotics used in combination. These findings identify DosRS as a potential therapeutic target in M. abscessus for which repurposed antimalarial drugs may be used therapeutically.
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