Development of potential proteasome inhibitors againstMycobacterium tuberculosis

Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the world. TB causing bacteria,Mycobacterium tuberculosishas become resistant to the first line of treatment along with second line of treatment and drugs, which are accessible to us. Thus, there is an urgent need of identification of key targets and development of potential therapeutic approach(s), which can overcome theMycobacterium tuberculosiscomplications. In the present study,Mycobacterium tuberculosisproteasome has been taken as a potential target as it is one of the key regulatory proteins inMycobacterium tuberculosispropagation. Further, a library of 400 compounds (small molecule) from Medicines for Malaria Venture (MMV) were screened against the target (proteasome) using molecular docking and simulation approach, and selected lead compounds were validated inin vitromodel. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with -9.8 kcal/mol and -8.7 kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain ofMycobacterium tuberculosisproteasome and inhibit theMycobacterium tuberculosisgrowth inin vitroculture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction withMycobacterium tuberculosiscompared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition inMycobacterium tuberculosisinin vitroandin vivomodel would eventually allow us to understand the molecular mechanism(s) and discover a novel and potent therapeutic agent against Tuberculosis. Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. Efflux pump activity was tested for a specific compound MMV019838 which was showing good in silico results than MIC values. Communicated by Ramaswamy H. Sarma

Automated summary

Tuberculosis is declared a health emergency due to the increasing problem of Multidrug-resistant Tuberculosis (MDR-TB) worldwide. This study identifies potential therapeutic approach against MDR-TB by screening small molecule compounds and validating their efficacy in inhibiting Mycobacterium tuberculosis growth. Molecular docking and simulation analysis show strong and stable interaction between the lead compounds and Mycobacterium tuberculosis proteasome, with no cytotoxicity effect on human proteasome.