Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

A search for novel approaches to improve Mycobacterium abscessus treatment outcome led to our interest in the two-component regulator DosRS which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of non-replicating, drug-tolerant, persistence in response to a variety of host stresses. We first show that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival following oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We next show that three antimalarial drugs or drug candidates - artemisinin, OZ277 and OZ439 - which we found to target DosS-mediated hypoxic signaling in M. abscessus recapitulate the phenotypic effects of genetically disrupting dosS. Importantly, OZ439 displays bactericidal activity comparable that of 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.