Journal
ACS INFECTIOUS DISEASES
Volume 7, Issue 2, Pages 273-280Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.0c00741
Keywords
M. tuberculosis; proteostasis; small molecule inhibitors; type-7 secretion system; ESX-1; virulence
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Funding
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2016-05730]
- National Sanitarium Association
- Devolved Graduate Scholarship from the Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan
- Devolved Graduate Scholarship from the Vaccinology and Immunotherapeutics Program, School of Public Health, University of Saskatchewan
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This study provides the first evidence of the importance of mycobacterial proteostasis to ESX-1 secretion system and identifies novel vulnerabilities in the ESX-1 system for potential anti-TB drug targets.
Mycobacterium tuberculosis (M. tb) uses its type-7 secretion system ESX-1 to translocate key virulence effector proteins. Taking a chemical genetics approach, we demonstrate for the first time the importance of mycobacterial proteostasis to ESX-1. We show that individual treatment with inhibitors of protein synthesis (chloramphenicol and kanamycin) and protein degradation (lassomycin and bortezomib), at concentrations that only reduce M. tb growth by 50% and less, specifically block ESX-1 secretion activity in the tubercle bacillus. In contrast, the mycobacterial cell-wall synthesis inhibitor isoniazid, even at a concentration that reduces M. tb growth by 90% has no effect on ESX-1 secretion activity. We also show that chloramphenicol but not isoniazid at subinhibitory concentrations specifically attenuates ESX-1-mediated M. tb virulence in macrophages. Taken together, the results of our study identify a novel vulnerability in the ESX-1 system and offer new avenues of anti-TB drug research to neutralize this critical virulence-mediating protein secretion apparatus.
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