Table_4_Mechanisms for Rapid Evolution of Carbapenem Resistance in a Clinical Isolate of Pseudomonas aeruginosa.XLS

Infections by Pseudomonas aeruginosa are difficult to cure due to its high intrinsic and acquired antibiotic resistance. Once colonized the human host, and thanks to antibiotic treatment pressure, P. aeruginosa usually acquires genetic mutations which provide bacteria with antibiotic resistance as well as ability to better adapt to the host environment. Deciphering the evolutionary traits may provide important insights into the development of effective combinatory antibiotic therapy to treat P. aeruginosa infections. In this study, we investigated the molecular mechanisms by which a clinical isolate (ISP50) yields a carbapenem-resistant derivative (IRP41). RNAseq and genomic DNA reference mapping were conducted to compare the transcriptional profiles and in vivo evolutionary trajectories between the two isolates. Our results demonstrated that oprD mutation together with ampC hyper-expression contributed to the increased resistance to carbapenem in the isolate IRP41. Furthermore, a ldcA (PA5198) gene, encoding murein tetrapeptide carboxypeptidase, has been demonstrated for the first time to negatively influence the ampC expression in P. aeruginosa.

铜绿假单胞菌（Pseudomonas aeruginosa）感染因其高固有耐药性与获得性耐药性而难以治愈。一旦定殖于人体宿主，加之抗生素治疗的选择压力，铜绿假单胞菌通常会获得基因突变，这些突变不仅赋予细菌抗生素耐药性，还使其更适应宿主环境。解析其进化特征，可为开发治疗铜绿假单胞菌感染的有效联合抗生素疗法提供重要思路。本研究针对一株临床分离株ISP50产生碳青霉烯耐药衍生株IRP41的分子机制展开探究。通过RNA测序（RNAseq）与基因组DNA参考比对技术，对比两株分离株的转录组表达谱与体内进化轨迹。研究结果显示，oprD基因突变联合ampC基因过表达，共同增强了分离株IRP41对碳青霉烯类抗生素的耐药性。此外，本研究首次证实，编码肽聚糖四肽羧肽酶的ldcA（PA5198）基因可负调控铜绿假单胞菌的ampC基因表达。