Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. In 2015, TB claimed 1.8 Million lives and 10 Million new infections occurred. Mycobacterium bovis BCG – introduced as vaccine against TB a century ago is the most widely used vaccine in the world however it only confers limited protection against adult lung TB. TB therapy is based on a four-drug regimen applied for 6 months. The long lasting therapy and the spread of multi-drug resistant TB strains indicate the urgent need for development of novel intervention strategies.
We recently characterized a M. bovis BCG zmp1 deletion mutant (deficient in synthesis of the metallopeptidase Zmp1). Zmp1 has structural similarity to two human proteases and is most active at a slightly acidic pH. BCG zmp1 induces inflammasome activation and is unable to arrest phagosome maturation. Relief from Zmp1-mediated phagosome maturation arrest is associated with facilitated antigen presentation and enhanced immunogenicity of mycobacterial antigens. Most importantly, BCG zmp1 confers a better protection than BCG against tuberculosis in animal models of infection. We continue to develop BCG zmp1 as a novel TB vaccine.
We recently applied a whole cell assay for screening a comprehensive chemical library in collaboration with our industrial partner, F. Hoffmann-La Roche Ltd. Promising hit compounds were identified and subjected to additional tests. Currently, we are characterizing these compounds for their specificity, toxicity and mode of action.