Asiaticoside A for the modulation of 1-TbAd- a potential target and ligand for extensive drug resistance Mycobacterium tuberculosis

Abstract

In nature, terpene nucleosides are relatively rare, with 1-tuberculosinyladenosine (1-TbAd) being an exclusive feature of Mycobacterium tuberculosis (Mtb). The convergence of nucleosides and terpene pathways in the Mtb complex appears to have emerged late in its evolutionary history. 1-TbAd (PDB ID: 3WQK) is a prominent chemical marker for Mtb and may contribute to its virulence-related properties when exported extracellularly. We gathered a comprehensive set of 270 phytochemicals from diverse Ayurvedic texts and treatment traditions. Subsequently, we conducted structure-based molecular docking analyses to identify compounds exhibiting the strongest binding affinity for 1-TbAd, highlighting their potential as drug candidates. These selected compounds were further subjected to an in-vitro growth inhibition assay against the reference strain Mycobacterium tuberculosis h37rv. Among the candidates, Asiaticoside A (ASA) emerged as a promising candidate from the pool of 270 compounds. To assess the impact of ASA on 1-TbAd expression, we employed a PCR-based mRNA expression assay, revealing ASA's ability to downregulate 1-TbAd expression in extensively drug-resistant MTb strains. Remarkably, the conventional drug rifampin showed no such effectiveness in our experiments. We further conducted molecular dynamic simulations to explore the interaction between ASA and 1-TbAd in a cellular-like environment, confirming the stability of their interaction. Also, we predicted ASA's stability toward causing inducing the random mutations in the target gene. With this, we propose a novel target and its modulator to treat extensively drug-resistant MTB. Graphical Abstract

New insight in molecular detection of Mycobacterium tuberculosis

“…The World Health Organization (WHO) has identified TB as the leading cause of death from a single infectious agent worldwide, surpassing even the human immunodeficiency virus (HIV) (Kasavandi et al 2023 ). MTB is the most prevalent infection and one of thirteen causes of mortality due to infections in the world (Meskini et al 2020 , 2021 ; Tilwani et al 2023 ). These alarming statistics underscore the pressing need for innovative diagnostic tools and approaches to enhance TB detection, treatment, and control.…”