New drugs to treat Tuberculosis

Tuberculosis (TB) remains a major health problem that affects billions of people worldwide each year. New strategies to treat and control this deadly disease are urgently needed. Critical to the ability of Mycobacterium tuberculosis (Mtb) to cause this disease is its ability to challenge the normal immune response and to avoid killing within host macrophages by blocking normal phagosomal maturation. Both strategies depend on the action of secreted virulence factors. Hence, an alternative approach to the use of classic antibiotics to treat TB is to block the action of such virulence factors. These include phosphoinositide phosphatases and kinases, which by manipulating of host phosphoinositide metabolism, contribute to the ability of Mtb to cause disease.

Our pioneering work on the characterization of one such virulence factor, the phosphoinositide phosphatase MptpB (Beresford 2007), suggested a role in phagosomal maturation arrest and thus offering an exciting new target for pharmacological intervention of TB. We also developed potent inhibitors of MptpB that impair the survival of Mtb in infected macrophages (Beresford 2009). Next, we want to use these inhibitors to further study the role of MptpB and another mycobacterial lipid phosphatase, SapM in pathogenesis and phagosomal maturation arrest.