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Small molecule disruption of the Mycobacterium tuberculosis proteostasis network inhibits the activity of the type-7 protein secretion system ESX-1

Kylee Drever (1,2) and Jeffrey M. Chen (1,2).
1 Vaccine and Infectious Disease Organization – International Vaccine Centre, University of Saskatchewan, Saskatoon, Canada
2 Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada

Mycobacterium tuberculosis (M. tb) uses its type-7 secretion system ESX-1 to translocate virulence effector proteins. Taking a chemical genetics approach, we demonstrate here for the first time the importance of mycobacterial proteostasis to ESX-1. We show that disruption of proteostasis with chloramphenicol, kanamycin, lassomycin and bortezomib, at concentrations that only reduce M. tb growth by 50% and less, potently block ESX-1 secretion activity in the tubercle bacillus. In contrast, the mycobacterial cell-wall synthesis inhibitor isoniazid, even at a concentration that reduces 90% of M. tb growth does not impact ESX-1 secretion activity. We also show that chloramphenicol but not isoniazid at sub-inhibitory concentrations specifically attenuates ESX-1-mediated M. tb virulence in macrophages. This study provides new insights into the workings of the ESX-1 system and identifies a new target for drug-mediated inhibition of this key virulence-mediating protein secretion apparatus.