Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

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

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

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FACFMIPA_abj3860_CombinedPDF_v5.pdf (19.22 MB)

Date

2022-02-23

Authors

Belardinelli, Juan Manuel, author

Verma, Deepshikha, author

Li, Wei, author

Avanzi, Charlotte, author

Wiersma, Crystal J., author

Williams, John T., author

Johnson, Benjamin K., author

Zimmerman, Matthew, author

Whittel, Nicholas, author

Angala, Bhanupriya, author

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.

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Pre-print manuscript.
Final version: Belardinelli JM, Verma D, Li W, Avanzi C, Wiersma CJ, Williams JT, Johnson BK, Zimmerman M, Whittel N, Angala B, Wang H, Jones V, Dartois V, de Moura VCN, Gonzalez-Juarrero M, Pearce C, Schenkel AR, Malcolm KC, Nick JA, Charman SA, Wells TNC, Podell BK, Vennerstrom JL, Ordway DJ, Abramovitch RB, Jackson M. Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus. Sci Transl Med. 2022 Feb 23;14(633):eabj3860. doi: 10.1126/scitranslmed.abj3860. Epub 2022 Feb 23. PMID: 35196022.
Includes bibliographical references.

Subject

antimalarial drugs

potent inhibitors

adjunct inhibitors

DosRS signaling

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https://hdl.handle.net/10217/234561

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Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

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