Polypharmacological Drug Repurposing Approach to Target Mycobacterium Tuberculosis

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB) is constantly evolving to multi-drug resistance (MDR) and extremely drug-resistance (XDR). Few MDR strains have also shown resistance against Bedaquiline, the recent drug introduced to treat MDR-TB. This emergent situation poses necessity to search novel drug targets/drug candidates or to repurpose existing drugs against known targets through Drug Repurposing. Repurposing has been earlier successful in many orphan indications such as cancer, leishmaniasis, rheumatoid arthritis, etc through combination of reverse pharmacology and computational biology approaches. In a more rational repurposing approach, we have combined drug repositioning with polypharmacology in order to modulate structure-function of multiple protein targets in M.tb using single drug or in combinations. Based on essentiality of genes established by Himar1-based transposon mutagenesis and sequencing of Himar1-based transposon mutagenesis studies in M. tb, three proteins were identified as potential drug targets. These included proteins essential in various homeostatic processes of the pathogen as replication machinery (RipA), chaperone assisted folding (MoxR1) and protein folding accelerator (PpiB). Using dual receptor based and receptor-template based screening protocols, we have identified potential candidates from FDA approved database of ~1900 drugs, which can potentially bind and modulate structure-function function of these targets, thereby inhibiting their activities. The identified drugs were observed to form strong H-bond network within the active site pocket of the targets. This was also confirmed though all atom molecular dynamics simulations for all drug-target complexes. High score of candidates against the protein targets and stability of inter-molecular network observed in MD simulations highlights possibility of these drugs as potential anti-TB agents.