Department of Biomedical Engineering and Sciences, School of Mechanical & Manufacturing Engineering, National University of Science & Technology, Islamabad, Pakistan.
School of Interdisciplinary Engineering & Sciences (SINES), National University of Science & Technology, Islamabad, Pakistan.
PLoS One. 2024 Jun 25;19(6):e0303285. doi: 10.1371/journal.pone.0303285. eCollection 2024.
Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure. The rise of multidrug-resistant strains of S. typhi exacerbates this challenge, severely compromising conventional treatment efficacy due to over activity of efflux pumps. In our study, a comprehensive exploration of two fundamental aspects to combat MDR in S. typhi is carried out; i.e. employing advanced bioinformatics analyses and AlphaFold AI, We successfully identified and characterised a putative homologue, ABC-TPA, reminiscent of the P-glycoprotein (P-gp) known for its role in multidrug resistance in diverse pathogens. This discovery provides a critical foundation for understanding the potential mechanisms driving antibiotic resistance in S. typhi. Furthermore, employing computational methodologies, We meticulously assessed the potential of lignans, specifically Schisandrin A, B, and C, as promising Efflux Pump Inhibitors (EPIs) against the identified P-gp homologue in S. typhi. Noteworthy findings revealed robust binding interactions of Schisandrin A and B with the target protein, indicating substantial inhibitory capabilities. In contrast, Schisandrin C exhibited instability, showing varied effectiveness among the evaluated lignans. Pharmacokinetics and toxicity predictions underscored the favourable attributes of Schisandrin A, including prolonged action duration. Furthermore, high systemic stability and demanished toxicity profile of SA and SB present their therapeutic efficacy against MDR. This comprehensive investigation not only elucidates potential therapeutic strategies against MDR strains of S. typhi but also highlights the relevance of computational approaches in identifying and evaluating promising candidates. These findings lay a robust foundation for future empirical studies to address the formidable challenges antibiotic resistance poses in this clinically significant infectious diseases.
伤寒，由伤寒沙门氏菌引起，对全球健康构成重大威胁，尤其是在医疗基础设施有限的地区。由于外排泵过度活跃，多重耐药菌株的出现使这一挑战更加严重，严重影响了常规治疗的效果。在我们的研究中，对伤寒中 MDR 的两个基本方面进行了全面的探索；即利用先进的生物信息学分析和 AlphaFold AI，我们成功地识别并描述了一个假定的同源物，ABC-TPA，类似于众所周知的 P-糖蛋白（P-gp），它在多种病原体的多药耐药中起作用。这一发现为理解驱动伤寒中抗生素耐药的潜在机制提供了关键基础。此外，我们还采用计算方法，仔细评估了木脂素，特别是五味子甲素、五味子乙素和五味子丙素，作为潜在的外排泵抑制剂（EPIs），针对鉴定出的伤寒中 P-gp 同源物。值得注意的发现表明，五味子甲素和五味子乙素与靶蛋白具有强大的结合相互作用，表明具有很强的抑制能力。相比之下，五味子丙素表现出不稳定性，在所评估的木脂素中表现出不同的有效性。药代动力学和毒性预测强调了五味子甲素的良好特性，包括延长作用持续时间。此外，SA 和 SB 的高系统稳定性和降低的毒性特征表明它们对 MDR 具有治疗效果。这项全面的研究不仅阐明了针对伤寒 MDR 菌株的潜在治疗策略，还强调了计算方法在识别和评估有前途的候选药物方面的重要性。这些发现为未来的经验研究奠定了坚实的基础，以应对抗生素耐药性在这种具有临床意义的传染病中带来的巨大挑战。
