Tilwani Komal, Patel Abhishek, Patel Mainavi, Sojitra Pankaj, Dave Gayatri
P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, 388421, India.
QxP Pharma project and GMP services Private Ltd, Ahmedabad, India.
AMB Express. 2023 Oct 13;13(1):111. doi: 10.1186/s13568-023-01616-w.
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.
在自然界中，萜烯核苷相对罕见，1-结核糖基腺苷（1-TbAd）是结核分枝杆菌（Mtb）的独特特征。Mtb复合体中核苷和萜烯途径的融合似乎在其进化历史后期才出现。1-TbAd（蛋白质数据银行ID：3WQK）是Mtb的一个显著化学标志物，当它被分泌到细胞外时，可能有助于其与毒力相关的特性。我们从各种阿育吠陀文献和治疗传统中收集了一套全面的270种植物化学物质。随后，我们进行了基于结构的分子对接分析，以确定对1-TbAd具有最强结合亲和力的化合物，突出它们作为候选药物的潜力。这些选定的化合物进一步针对参考菌株结核分枝杆菌h37rv进行了体外生长抑制试验。在这些候选物中，积雪草苷A（ASA）从270种化合物中脱颖而出，成为一个有前景的候选物。为了评估ASA对1-TbAd表达的影响，我们采用了基于PCR的mRNA表达测定法，揭示了ASA在广泛耐药的MTb菌株中下调1-TbAd表达的能力。值得注意的是，传统药物利福平在我们的实验中没有显示出这种效果。我们进一步进行了分子动力学模拟，以探索ASA和1-TbAd在类似细胞环境中的相互作用，证实了它们相互作用的稳定性。此外，我们预测了ASA对靶基因诱导随机突变的稳定性。据此，我们提出了一种治疗广泛耐药MTB的新靶点及其调节剂。
