鲍曼不动杆菌转录调控元件毒力因子的作用机制研究

鲍曼不动杆菌是临床检出率极高且导致严重肺炎、血流和术后继发感染的多重耐药病原菌。目前其多重耐药的机制研究已取得显著进展，而其高临床检出率以及如何致病和免疫逃逸的分子机制还不清晰。本项目将研究鲍曼不动杆菌耐受临床灭菌剂醋酸氯已定以及介导其感染模型存活率的多个转录调控毒力因子的作用机制。我们将筛查临床感染样本中转录调控毒力因子的基因突变和多态性；进一步通过一体化结构生物学方案，解析这些转录调控毒力因子在未激活，激活以及识别靶向调控DNA序列的结构分子机制；最后构建基因敲除和点突变菌株，利用小鼠和蜡螟病原宿主感染模型，验证临床感染样本中的多态性和结构机制获得的关键调控氨基酸位点对其临床环境耐受和病原宿主相互作用的影响。在临床、结构和病原宿主感染模型多个尺度揭示鲍曼不动杆菌转录调控毒力因子介导其临床环境耐受和致病的作用机制，为寻找特异靶向多重耐药鲍曼不动杆菌新的抗生素药物和抗感染治疗手段提供依据。

Acinetobacter baumannii is a multidrug resistant pathogen with high clinical ICU detection rate, which can cause severe pneumonia, blood stream infection and secondary infections after surgery. Most of the research in Acinetobacter baumannii has been focusing on the mechanism of its multidrug resistance and has made significant progress. However, the molecular mechanism of its high clinical detection rate and pathogenesis of how Acinetobacter baumannii escape from the host immune system remain elusive..This project will investigate the mechanism of how Acinetobacter baumannii can tolerant the clinically sterilized Chlorhexidine acetate and how it can survive under the immune system of the infection model. Firstly, we will screen the genetic mutations and polymorphisms of those transcriptional regulatory virulence factors from the clinical isolated Acinetobacter baumannii samples. Then we will carry out an integrative structural biology approach to reveal the structural insight of these transcriptional regulatory virulence factors in inactive, activated and in recognition with their target regulatory DNA sequence. Finally, we will make the knockout and point mutation Acinetobacter baumannii strains, together with the mouse and Galleria mellonella Acinetobacter baumannii infection model to verify the molecular mechanism in vivo..Taken together, we will apply the clinical, structural and infectious model study to demonstrate the molecular mechanism into how the transcriptional regulatory virulence factors involve in the tolerance of Chlorhexidine acetate and escape from the host immune system. The study will provide insight and enlighten the antimicrobial drug discovery and anti-infective strategy against the multidrug resistant Acinetobacter baumannii.