Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in <i>Mycobacterium abscessus</i>

Abstract

A search for alternative <i>Mycobacterium abscessus</i> treatments led to our interest in the two-component regulator DosRS, which, in <i>Mycobacterium tuberculosis</i>, 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 <i>dosRS</i> impairs the adaptation of <i>M. abscessus</i> 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 <i>M. abscessus</i> and recapitulate the phenotypic effects of genetically disrupting <i>dosS</i>. 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 <i>M. abscessus</i> in vivo offers repurposing opportunities that could have an immediate impact in the clinic.