Zhu Zhen, Zhou Xuzheng, Li Bing, Wang Sihan, Cheng Fusheng, Zhang Jiyu
Key Laboratory of New Animal Drug Project of Gansu Province, Key Laboratory of Veterinary Pharmaceutical Development of Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Sciences , CAAS, Lanzhou, People's Republic of China .
Microb Drug Resist. 2018 Apr;24(3):323-336. doi: 10.1089/mdr.2016.0173. Epub 2017 Aug 30.
Shigella flexneri is one of the most prominent pathogenic bacteria in developing countries. In the battle against shigellosis and other bacterial diseases, antibiotic resistance has become an increasing global public health threat. Although the serious phenomenon of multidrug resistance (MDR) has been identified as one of the top three burdens on human health, resistance mechanisms are still poorly understood at the molecular level. In this study, we analyzed genomic data and the evolution of resistance in Shigella flexneri under sequential selection stress from three separate antibiotics: ciprofloxacin (CIP), ceftriaxone (CRO), and tetracycline. Through whole-genome sequencing, 82 chromosomal antibiotic resistance genes were identified. Re-sequencing of the evolved populations identified single nucleotide polymorphisms (SNPs) that contributed to MDR and SNPs that were specific to a single drug. A total of 40 SNPs in 8 genes and 3 intergenic regions, including mutations in metG (L582R) and 1538924, 1538924, and 1538924, appeared under each antibiotic. Several nonsynonymous mutations in gyrB (S464Y), ydgA (E378A), rob (R156H), and narX (K75E) were observed under selective pressure from CIP or CRO. Based on a bioinformatic analysis and previous reports, we discuss the contribution of these mutated genes to resistance. Therefore, more circumspect selection and use of antimicrobial drugs for treating shigellosis is necessary.
福氏志贺菌是发展中国家最主要的病原菌之一。在对抗志贺菌病和其他细菌性疾病的斗争中，抗生素耐药性已成为日益严重的全球公共卫生威胁。尽管多重耐药（MDR）这一严重现象已被确定为人类健康面临的三大负担之一，但在分子水平上对耐药机制仍知之甚少。在本研究中，我们分析了福氏志贺菌在来自三种不同抗生素（环丙沙星（CIP）、头孢曲松（CRO）和四环素）的连续选择压力下的基因组数据和耐药性演变。通过全基因组测序，鉴定出82个染色体抗生素耐药基因。对进化群体的重测序确定了导致MDR的单核苷酸多态性（SNP）和特定于单一药物的SNP。在每种抗生素作用下，8个基因和3个基因间区域共出现40个SNP，包括metG（L582R）以及1538924、1538924和1538924处的突变。在CIP或CRO的选择压力下，观察到gyrB（S464Y）、ydgA（E378A）、rob（R156H）和narX（K75E）中的几个非同义突变。基于生物信息学分析和先前的报道，我们讨论了这些突变基因对耐药性的贡献。因此，治疗志贺菌病时更谨慎地选择和使用抗菌药物是必要的。
