鲍曼不动杆菌舒巴坦耐药新机制研究

鲍曼不动杆菌已成为医院感染的主要病原菌之一，舒巴坦作为治疗鲍曼不动杆菌感染的重要抗菌药物，近年来耐药率明显增加，但其耐药机制的研究很少。ftsI基因突变及TEM-1酶高表达是目前已知的最主要耐药机制，但此机制只能解释临床分离菌的少数耐药现象，本课题前期亦发现此机制与舒巴坦耐药水平无明显相关性，极有可能存在新的机制。利用基因组重测序及比较基因组学技术，前期已在ATCC17978及ZJ06舒巴坦体外诱导耐药株中发现了ftsZ及ponA基因的突变可能与舒巴坦耐药相关。本课题拟在完成已知耐药机制在临床分离菌舒巴坦耐药中作用的基础上，通过基因敲除及回补技术明确ftsZ及ponA突变基因的功能；进一步运用转录组测序技术在诱导耐药菌中发现新的差异表达基因，明确其耐药相关功能，并在临床分离菌中进行验证，从而系统阐明鲍曼不动杆菌舒巴坦的耐药机制，为临床舒巴坦耐药鲍曼不动杆菌的防治提供基础。

Acientobacter baumannii has emerged as one of the most important pathogens associated with nosocomial infection. Sulbactam, one of the most effective antimicrobial agents against A. baumannii infection, is confronted with difficulties of increasing resistant rate in recent years. Studies on the resistant mechanisms are few except for the mutation of ftsI gene and high expression of TEM-1-type β-lactamase. However, both published studies as well as our previous findings supported that the above mechanisms showed few contributions to clinical sulbactam-resistant strains and were irrelevant with the resistant levels of sulbactam. So there most likely have some novel unrevealed mechanisms associated with the sulbactam resistance. By using high-throughput genome sequencing technology on the induced sulbactam resistant strains of ATCC17978 and ZJ06, our previous findings revealed that the mutations of ftsZ and ponA gene might be contributed to the sulbactam resistance. This study will verify the functions of the mutant ftsI gene and the high expression of TEM-1-type β-lactamase in clinical strains and concentrate on the novel mutant genes. We prefer to further discover some novel differential expressed genes by comparing the differences of transcriptome data between ATCC17978/ ZJ06 and their induced resistant strains, reveal the functions of mutant genes (ftsZ and ponA) and the novel differential expressed genes in the induced resistant strains by gene knockout and complementation experiment. We will further clarify the functions of the mutant genes and the novel differential expressed genes in clinical A. baumannii strains with different sulbactam MICs levels. Overall, we hope to systematically identify the resistant mechanisms of sulbactam to A. baumannii and finally provide evidence on the control of clinical sulbactam resistant-A. baumannii strains.