Chen Mo, Li Yanhua, Li Shu, Cui Wenqiang, Zhou Yonghui, Qu Qianwei, Che Ruixiang, Li Lu, Yuan Shuguang, Liu Xin
College of Veterinary Medicine, Northeast Agricultural University, Harbin, People's Republic of China.
Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Shenzhen, People's Republic of China.
Infect Drug Resist. 2022 Oct 26;15:6165-6176. doi: 10.2147/IDR.S379264. eCollection 2022.
Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs. Strains that are resistant to multiple drugs pose severe clinical problems and cost lives. However, systematic studies on cross-resistance of have been missing.
Here, we investigated various mutations in the sequence of ribosomal proteins involved in cross-resistance. To understand this effect on a molecular basis and to further elucidate the role of cross-resistance, we computationally constructed the 3D model of the large ribosomal subunit from as well as its complexes with both tylosin and florfenicol. Meanwhile, all-atom molecular dynamics simulations was used. In addition, the regulation of protein networks also played an essential role in the development of cross-resistance in .
We discovered that the minimum inhibitory concentration against both tylosin and florfenicol of the mutant strain containing the insertion L22 97KRTSAIN98 changed dramatically. Further, we found that unique structural changes in the β-hairpin of L22 played a central role in this variant in the development of antibiotic resistance in . The regulation of protein networks also played an essential role in the development of cross-resistance in .
Our work provides insightful views into the mechanism of resistance that could be useful for the development of the next generation of antibiotics.
耐药性对全球公共卫生构成了日益严重的威胁，涉及所有主要的微生物病原体和抗菌药物。对多种药物耐药的菌株会引发严重的临床问题并危及生命。然而，关于[具体对象]交叉耐药性的系统性研究一直缺失。
在此，我们研究了参与交叉耐药性的核糖体蛋白序列中的各种突变。为了从分子层面理解这种效应并进一步阐明交叉耐药性的作用，我们通过计算构建了来自[具体对象]的大核糖体亚基的三维模型及其与泰乐菌素和氟苯尼考的复合物模型。同时，使用了全原子分子动力学模拟。此外，蛋白质网络的调控在[具体对象]交叉耐药性的发展中也起着至关重要的作用。
我们发现含有插入序列L22 97KRTSAIN98的突变菌株对泰乐菌素和氟苯尼考的最低抑菌浓度发生了显著变化。此外，我们发现L22的β-发夹结构中的独特结构变化在该变体对[具体对象]抗生素耐药性的发展中起核心作用。蛋白质网络的调控在[具体对象]交叉耐药性的发展中也起着至关重要的作用。
我们的工作为[具体对象]耐药机制提供了深刻见解，这可能有助于下一代抗生素的研发。
