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- Title
Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus.
- Authors
Belardinelli, Juan Manuel; Verma, Deepshikha; Li, Wei; Avanzi, Charlotte; Wiersma, Crystal J.; Williams, John T.; Johnson, Benjamin K.; Zimmerman, Matthew; Whittel, Nicholas; Angala, Bhanupriya; Wang, Han; Jones, Victoria; Dartois, Véronique; de Moura, Vinicius C. N.; Gonzalez-Juarrero, Mercedes; Pearce, Camron; Schenkel, Alan R.; Malcolm, Kenneth C.; Nick, Jerry A.; Charman, Susan A.
- 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. Repurposed antimalarials: 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.
- Subjects
DRUG efficacy; MYCOBACTERIUM tuberculosis; ANTIMALARIALS; TREATMENT effectiveness; MYCOBACTERIUM; ANTIBIOTICS; ARTEMISININ
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 633, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abj3860