While short course chemotherapy for drug-susceptible tuberculosis (TB) remains effective, it is relatively inefficient by modern pharmaceutical standards and universally menaced by the dissemination of multidrug-resistant (MDR), extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (M.tb) and synergy with the HIV/AIDS pandemic. Since one third of the world’s population is latently infected with M.tb, successful anti-TB drugs must be able to eliminate persistent bacilli from the reservoir, which makes TB therapy more challenging.Most of the current antibiotics typically kill M.tb rather than targeting bacterial systems important in the virulence of the bacteria and manipulation of the host-specific biochemical pathways.Whereas normally the host immune system is able to destroy invading bacilli, M.tb developed a wide palette of strategies to avoid bactericidal host responses. The major and most studied virulence mechanism of the tuberculosis pathogen is the ESX-1 system, a type VII secretion system which clearly plays an important role in the pathogenicity and the host-pathogen interaction. The ESX-1 system modulates the host defence through different ways like phagosome maturation arrest, inhibition of TLR signalling in macrophages, macrophage apoptosis induction, and interaction with laminin.The here proposed project forms part of a multidisciplinary anti-virulence drug discovery program focusing on the identification of important host cell signalling pathways that are involved in the pathogenesis, entry and intracellular survival of M.tb. Anti-virulence drugs inhibit bacterial targets that interfere with host cell defence pathways during infection or block host signalling pathways modulated by the bacteria, thus defending the host from the pathogen. This novel strategy of anti-virulence drug discovery is a potential alternative to antibiotics, which may be used in combination therapies to shorten TB treatment and prevent resistance.