Development of multiple kinase target (MuKiT) inhibitors for treating tuberculosis – MuKit

Tuberculosis is one of the oldest diseases known to man and it remains today as a major health problem, with one-third of the world’s population being infected by Mycobacterium tuberculosis. Global tuberculosis control is facing major challenges, primarily due to the emergence of multi-drug resistant (MDR and XDR) TB, the co-infection with M. tuberculosis and HIV and the difficulties to treat latent TB infection. Furthermore, much effort is still required to make quality care accessible without barriers of gender, age, type of disease, social setting, and ability to pay. There is an extremely urgent need to identify bactericidal compounds that have intra- and extracellular activities with rapid-kill kinetics and that have an extended safety profile. Due to the heterogeneity of the bacterial population in the host and the drug-drug interactions in the prolonged therapy, development of new drug candidates is very challenging. Protein kinases are attractive and crucial therapeutic targets for the design of small molecules capable of specifically inhibiting either host cell or pathogen kinases in the course of TB infections. Based on already published target-hit pairs and previously identified PknG lead molecules, we will focus on the discovery of potential inhibitors against multiple kinase targets combining both whole-cell screening and target-based screening assays. The inhibitor-target protein complexes will be crystallised and their 3D structures determined to guide the drug design effort. The biological effect of new compounds will be determined in both in vitro kinase as well as bacterial assays. ADME-T studies of potent lead molecules will be performed and their off-target profile will be also determined. If successful, the project will produce a wide variety of knowledge and experience, which can be useful for further investigations in the field of fundamental and applied research on TB infection and disease.