Towards anti-virulence drugs targeting ESX-1 mediated pathogenesis of Mycobacterium tuberculosis

The control of tuberculosis (TB) in humans is heavily reliant on short course chemotherapy yet this intervention is increasingly menaced by widespread multi- and extensively drug resistant strains of Mycobacterium tuberculosis. New druggable targets and novel leads are required for TB drug discovery to develop compounds with greater potency, and that are less prone to acquired drug resistance. As such, the concept of blocking the secretion of virulence proteins and modulating their effect with small molecules has gained increasing attention in recent years. Here, we propose targeting the principal virulence determinant of M. tuberculosis, the ESX-1 protein secretion system and its downstream effects, to discover new drugs and augment the dwindling armoury of effective antitubercular agents.