Syeda Farishta, Rani Faryal, Muhammad Waqas, Muhammad Ali, Rizwan Uppal, Muhammad Salman, Zurva Ashraf, Asaad Khalid, Ajmal Khan
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引用次数: 0
Abstract
The widespread use of azithromycin during the COVID-19 pandemic has likely contributed to the increased resistance of Salmonella Typhi to this antibiotic. This study focuses on the extensive drug resistance (XDR) of Salmonella Typhi in Pakistan, analyzing 11,916 suspected typhoid fever cases, with 424 confirmed as Salmonella Typhi and Paratyphi A. Through antimicrobial susceptibility tests and PCR-based Sanger sequencing, an R717L mutation in the AcrB gene was identified, signalling the emergence of azithromycin resistance. This mutation was notably prevalent among XDR Salmonella Typhi isolates, with a high detection of blaCTX-M gp 1 (93%), followed by blaCTX-M 2 (87%) and blaTEM (81%). Detailed analysis revealed that the R717L mutation significantly alters the AcrB protein's interaction with azithromycin, evidenced by lower docking scores and reduced critical interactions, thus diminishing the antibiotic's affinity. Molecular Dynamics (MD) simulations further demonstrated that this mutation induces considerable structural changes in AcrB, impacting its stability and conformation. Additionally, binding free energy calculations showed decreased binding affinity of azithromycin to the mutated AcrB protein. These findings underscore the critical role of the R717L mutation in conferring drug resistance and highlight the urgent need for developing new antibiotic strategies to combat this growing threat. The evolution of azithromycin resistance in XDR Salmonella Typhi underscores the importance of cautious antibiotic use and the necessity for ongoing surveillance and research to inform effective typhoid fever treatment protocols.
在2019冠状病毒病大流行期间,阿奇霉素的广泛使用可能导致伤寒沙门氏菌对这种抗生素的耐药性增强。本研究重点关注巴基斯坦伤寒沙门菌的广泛耐药(XDR),分析了11,916例疑似伤寒病例,其中424例确诊为伤寒沙门菌和甲型副伤寒沙门菌。通过药敏试验和基于pcr的Sanger测序,鉴定出AcrB基因R717L突变,标志着阿奇霉素耐药性的出现。该突变在XDR伤寒沙门氏菌分离株中普遍存在,其中blaCTX-M gp 1的检出率较高(93%),其次是blactx - m2(87%)和blaTEM(81%)。详细分析表明,R717L突变显著改变了AcrB蛋白与阿奇霉素的相互作用,其对接评分降低,临界相互作用减少,从而降低了抗生素的亲和力。分子动力学(MD)模拟进一步表明,这种突变引起AcrB的相当大的结构变化,影响其稳定性和构象。此外,结合自由能计算显示阿奇霉素与突变AcrB蛋白的结合亲和力降低。这些发现强调了R717L突变在赋予耐药性方面的关键作用,并强调了开发新的抗生素策略来对抗这一日益增长的威胁的迫切需要。广泛耐药伤寒沙门氏菌中阿奇霉素耐药性的演变强调了谨慎使用抗生素的重要性,以及持续监测和研究的必要性,以便为有效的伤寒治疗方案提供信息。
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.