Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus

被引：25

作者：

Belardinelli, Juan Manuel ^{[1
]}

Verma, Deepshikha ^{[1
]}

Li, Wei ^{[1
]}

Avanzi, Charlotte ^{[1
]}

Wiersma, Crystal J. ^{[1
]}

Williams, John T. ^{[2
]}

Johnson, Benjamin K. ^{[3
]}

Zimmerman, Matthew ^{[4
]}

Whittel, Nicholas ^{[1
]}

Angala, Bhanupriya ^{[1
]}

Wang, Han ^{[4
]}

Jones, Victoria ^{[1
]}

Dartois, Veronique ^{[4
]}

de Moura, Vinicius C. N. ^{[1
,11
]}

Gonzalez-Juarrero, Mercedes ^{[1
]}

Pearce, Camron ^{[1
]}

Schenkel, Alan R. ^{[5
]}

Malcolm, Kenneth C. ^{[6
,7
]}

Nick, Jerry A. ^{[6
,7
]}

Charman, Susan A. ^{[8
]}

Wells, Timothy N. C. ^{[9
]}

Podell, Brendan K. ^{[1
]}

Vennerstrom, Jonathan L. ^{[10
]}

Ordway, Diane J. ^{[1
]}

Abramovitch, Robert B. ^{[2
]}

Jackson, Mary ^{[1
]}

机构：

[1] Colorado State Univ, Mycobacteria Res Labs, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA

[2] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI USA

[3] Van Andel Inst, Dept Epigenet, Grand Rapids, MI USA

[4] Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ USA

[5] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA

[6] Natl Jewish Hlth, Dept Med, Denver, CO USA

[7] Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA

[8] Monash Univ, Ctr Drug Candidate Optimisat, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia

[9] Med Malaria Venture, Geneva, Switzerland

[10] Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE USA

[11] Natl Jewish Hlth, NTM Culture Biorepository & Coordinating Core, Denver, CO USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2022年 / 14卷 / 633期

基金：

欧盟地平线“2020”;

关键词：

CYSTIC-FIBROSIS; NONTUBERCULOUS MYCOBACTERIA; PSEUDOMONAS-AERUGINOSA; BIOFILM FORMATION; TUBERCULOSIS; SUSCEPTIBILITY; MACROPHAGES; ENVIRONMENT; INFECTIONS; ADAPTATION;

D O I：

10.1126/scitranslmed.abj3860

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：14

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