A novel in-silico strategy for the combined inhibition of intestinal bacterial resistance and the transfer of resistant genes using new fluoroquinolones, antibiotic adjuvants, and phytochemicals

IF 4.8 1区 农林科学 Q1 FOOD SCIENCE & TECHNOLOGY Food Bioscience Pub Date : 2024-09-05 DOI:10.1016/j.fbio.2024.105036
Qikun Pu , Zhonghe Wang , Tong Li , Qing Li , Meijin Du , Wenwen Wang , Yu Li
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Abstract

The antibiotic resistance and transfer of antibiotic resistance genes (ARGs) lead to severe environmental threats, and efficient regulatory measures to solve the above problems are urgently needed. Thus, a novel three-dimensional quantitative structure-activity relationship for S. aureus antibiotic resistance was constructed in this study. A fluoroquinolone (FQ) substitute (CIP-098) with decreased bacterial resistance by 15.19% and antibiotic adjuvant (2-phenylquinoline efflux pump inhibitor (2P-Q-EPI) substitute (Z-20)) that enhanced efflux pump inhibition by 1.96 times were designed. Mechanism analysis revealed that hydrogen bond donors and hydrogen bonding in FQ are essential groups and non-covalent interactions, which assist antibiotics in combating resistance mutations in S. aureus's DNA gyrase that transition from hydrophilic to hydrophobic residues. Z-20 was found to easily bind to key amino acid residues (Phe-16, Ile-19), thus reducing the antibiotic expulsion by the NorA efflux pump protein, which can inhibit antibiotic resistance in bacteria. The non-antibiotic factor regulatory scheme designed in this study significantly reduced (by 39.70%) the efflux of FQ by S. aureus and the risk of horizontal ARGs transfer. This study proposes a new strategy to mitigate FQ antibiotic resistance and ARGs transfer in gut microbiota, offering technical support for the green development of FQ antibiotics and 2P-Q-EPI.

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利用新型氟喹诺酮类药物、抗生素佐剂和植物化学物质联合抑制肠道细菌耐药性和耐药基因转移的新型分子内策略
抗生素耐药性和抗生素耐药基因(ARGs)的转移导致了严重的环境威胁,迫切需要有效的监管措施来解决上述问题。因此,本研究构建了金黄色葡萄球菌抗生素耐药性的新型三维定量结构-活性关系。设计出了可降低细菌耐药性 15.19% 的氟喹诺酮(FQ)替代物(CIP-098)和可增强外排泵抑制作用 1.96 倍的抗生素辅助剂(2-苯基喹啉外排泵抑制剂(2P-Q-EPI)替代物(Z-20))。机理分析表明,FQ 中的氢键供体和氢键是必不可少的基团和非共价相互作用,有助于抗生素对抗金黄色葡萄球菌 DNA 回旋酶中从亲水残基过渡到疏水残基的耐药性突变。研究发现,Z-20 很容易与关键氨基酸残基(Phe-16、Ile-19)结合,从而减少 NorA 外排泵蛋白对抗生素的排出,从而抑制细菌对抗生素的耐药性。本研究设计的非抗生素因子调控方案大大降低了(39.70%)金黄色葡萄球菌对 FQ 的外排,并降低了 ARGs 水平转移的风险。该研究提出了一种缓解肠道微生物群中 FQ 抗生素耐药性和 ARGs 转移的新策略,为 FQ 抗生素和 2P-Q-EPI 的绿色开发提供了技术支持。
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来源期刊
Food Bioscience
Food Bioscience Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
6.40
自引率
5.80%
发文量
671
审稿时长
27 days
期刊介绍: Food Bioscience is a peer-reviewed journal that aims to provide a forum for recent developments in the field of bio-related food research. The journal focuses on both fundamental and applied research worldwide, with special attention to ethnic and cultural aspects of food bioresearch.
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