Leveraging Pan-Genomics, Subtractive Proteomics and Molecular Modeling to Identify Potential Drug Targets and Phytochemical Inhibitors for Leprosy Treatment

Mycobacterium leprae (M. leprae), the etiological agent of leprosy or Hansen’s disease, manifests as a spectrum of clinical symptoms, ranging from skin lesions to severe disfigurement and neurological deficits. With the alarming rise of bacterial resistance, particularly in strains of M. leprae, delving into its pan-genome becomes imperative. This exploration not only illuminates its evolutionary trajectories but also provides critical insights into mechanisms of drug resistance. In our research, we adopted an integrated approach combining pan-genomics and subtractive proteomics, offering a comprehensive understanding of the bacterium’s evolutionary dynamics and highlighting potential therapeutic avenues. Pan-genome analysis of four M. leprae strains revealed a set of 3030 core genes. These underwent a series of subtractive proteomics evaluations considering nonhuman homology, virulence association, bacterial essentiality, metabolic pathway participation and further gene-enrichment analysis. Through subtractive proteomics analysis, the HU family DNA binding protein was identified as a core drug target of M. leprae. To further our investigation, molecular docking methodologies were applied to this protein target, testing its interactions with a curated suite of phytochemical ligands. Notably, five of these ligands — Azadiradione, 2-(1-Hydroxyethyl)naphtho(2,3-b)furan-4,9-dione, Tanshinone IIA, Gancaonin I and Balsaminone A — emerged as having significant potential inhibitory effects against M. leprae. Molecular dynamics simulations and MM-PBSA further revealed Balsaminone A and Tanshinone IIA as potent inhibitors with a total binding energy −10.57 and −14.9 kcal/mol, respectively. While our findings mark a promising step forward in the search for innovative therapeutic strategies against leprosy, it is crucial to note the importance of subsequent in vitro studies. Such studies are needed to rigorously validate the real-world effectiveness and safety of these potential drug targets and inhibitors.