Protein Synthesis and Degradation Inhibitors Potently Block Mycobacterium tuberculosis type-7 Secretion System ESX-1 Activity

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.