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《工程(英文)》 >> 2022年 第9卷 第2期 doi: 10.1016/j.eng.2020.12.015

猪链球菌中发现可介导链阳菌素A、截短侧耳素类以及林可酰胺类药物耐药的新型耐药基因 srpA

a College of Veterinary Medicine, China Agricultural University, Beijing, China
b Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety and Beijing Laboratory for Food Quality and Safety, China Agricultural University, Beijing, China

收稿日期: 2020-08-05 修回日期: 2020-11-13 录用日期: 2020-12-02 发布日期: 2021-02-24

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摘要

细菌耐药性问题毫无疑问是全球最大的健康威胁之一。耐甲氧西林的金黄色葡萄球菌、耐万古霉素的屎肠球菌和耐β-内酰胺的肺炎链球菌等多重耐药革兰氏阳性菌的出现,严重限制了临床可用的抗菌药物。截短侧耳素类、恶唑烷酮类以及链阳霉素类等许多靶向核糖体的抗菌药物,有望成为治疗这些多重耐药病原体的替代选择。本研究中,我们通过比较基因组学,在截短侧耳素类耐药猪链球菌中发现了一个新型耐药基因srpA。功能克隆试验显示该基因可以介导猪链球菌和金黄色葡萄球菌等对截短侧耳素类、林可酰胺类和链阳菌素A类抗菌药物的交叉耐药性。氨基酸序列比对显示SrpA与Vga(E)具有高度的同源性(36%),并显示出典型的ABC-F家族成员特征。分子对接试验显示SrpA 的loop 区域与肽基转移酶中心的截短侧耳素类结合口袋重合,并与截短侧耳素类竞争结合该位点。进一步研究发现SrpA 中loop 区的氨基酸突变或缺失将不同程度地影响细菌的耐药性,证实该结构域对SrpA 功能至关重要。药物胞内蓄积试验显示,SrpA不具有外排泵作用,而核糖体结合试验证明SrpA可以通过阻止抗菌药物与核糖体结合来保护核糖体。这些研究结果阐明了SrpA介导耐药的分子机制。

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