Tuberculosis

More than 2 billion people are infected with tuberculosis worldwide and the recent emerge of various multidrug resistant tuberculosis bacterial strains strongly increased the interest in novel antituberculotic drugs.

In our antituberculotic drug developmental program our primary target is PknG kinase, which is secreted by pathogenic mycobacteria, in macrophages to intervene with host cell signalling pathways to block the fusion of the lysosomes with the phagosome. Based on a biochemical PknG assay we have developed lead molecules with IC₅₀ values in nanomolar range, and demonstrated their antituberculotic effects on human macrophages. Selected leads might ultimately serve the purpose of inducing phagosomal-lysosomal fusion and therefore destroy the residence of the intracellular mycobacteria.

In order to kill even those Mycobacterias which are released from macrophages our secondary target is PKnB because mycobacteria rely on the essential function of PknB for survival. PknB is a transmembrane protein, responsible for cell growth and morphology. We have screened our library selected hits and generated a pharmacophore model for the inhibition of PknB. We have generated optimized hit compounds with nanomolar IC₅₀ values and currently work on hit to lead optimization.