Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

A search for alternative treatments led to our interest in the two-component regulator DosRS, which, in , 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 impairs the...

Full description

Saved in:
Bibliographic Details
Published in:Science translational medicine 2022-02, Vol.14 (633), p.eabj3860-eabj3860
Main 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, Wells, Timothy N C, Podell, Brendan K, Vennerstrom, Jonathan L, Ordway, Diane J, Abramovitch, Robert B, Jackson, Mary
Format: Article
Language:English
Subjects:
Antibiotics
Antimalarial agents
Artemisinin
Bactericidal activity
Biofilms
Drug delivery
Drug development
Hypoxia
Malaria
Mycobacterium abscessus
Oxygen depletion
Tuberculosis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A search for alternative treatments led to our interest in the two-component regulator DosRS, which, in , 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 impairs the adaptation of 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 and recapitulate the phenotypic effects of genetically disrupting . 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 in vivo offers repurposing opportunities that could have an immediate impact in the clinic.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.abj3860