Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

Juan Manuel Belardinelli, Deepshikha Verma, Wei Li, Charlotte Avanzi, Crystal J. Wiersma, John T. Williams, Benjamin K. Johnson, Matthew Zimmerman, Nicholas Whittel, Bhanupriya Angala, Han Wang, Victoria Jones, Véronique Dartois, Vinicius C.N. de Moura, Mercedes Gonzalez-Juarrero, Camron Pearce, Alan R. Schenkel, Kenneth C. Malcolm, Jerry A. Nick, Susan A. CharmanTimothy N.C. Wells, Brendan K. Podell, Jonathan L. Vennerstrom, Diane J. Ordway, Robert B. Abramovitch, Mary Jackson

Research output: Contribution to journalArticlepeer-review

Abstract

A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic.

Original languageEnglish (US)
Article numberabj3860
JournalScience translational medicine
Volume14
Issue number633
DOIs
StatePublished - Feb 23 2022

ASJC Scopus subject areas

  • Medicine(all)

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