Resistance to Carbapenem Antibiotics in Acinetobacter baumannii

 描述（由申请方提供）：β-内酰胺类抗生素代表了最大和临床上使用最多的抗菌剂家族。在革兰氏阴性菌中，β-内酰胺酶（能够破坏β-内酰胺的酶）的存在是严重的临床问题。这些酶的一个子集，碳青霉烯酶，强烈水解碳青霉烯类抗生素。碳青霉烯类是治疗危及生命的感染的最后手段。在所有四种分子类型的β-内酰胺酶（A、B、C和D类）中均鉴定出具有碳青霉烯酶活性的酶。D类碳青霉烯酶广泛分布在对其他可用类别的抗生素具有抗性的不动杆菌属和肠杆菌科分离株中，并且这些分离株具有耐药性。 产生碳青霉烯酶的细菌通常具有多药耐药性或甚至泛药耐药性。由这些病原体引起的感染很难治疗，有时甚至无法治疗。在这项资助申请中，我们将对A.鲍曼不动杆菌。这些酶广泛分布于临床A.鲍曼不动杆菌分离并将该病原体提升到最致命和最难治疗的类别，死亡率通常超过30- 50%。阐明了A.鲍曼不动杆菌CHDL的研究，并评估这些D类酶的进化潜力，以进一步增强其对碳青霉烯类的催化效率，使这类重要的抗生素在治疗由这种细菌病原体引起的感染中过时。最后，我们将设计和测试D类碳青霉烯酶的抑制剂，以恢复碳青霉烯类抗生素在对抗致命的A。鲍曼不动杆菌感染。

 DESCRIPTION (provided by applicant): ß-Lactam antibiotics represent the largest and clinically most used family of antibacterial agents. The existence of ß-lactamases, enzymes capable of destroying ß-lactams, in Gram-negative bacteria is a serious clinical problem. A subset of these enzymes, carbapenemases, hydrolyzes carbapenem antibiotics avidly. Carbapenems are drugs of last resort in treatment of life-threatening infections. Enzymes with carbapenemase activity have been identified in all four molecular classes of ß-lactamases (classes A, B, C and D). Class D carbapenemases are widely distributed in Acinetobacter and Enterobacteriaceae isolates that are resistant to other available classes of antibiotics, and these carbapenemase-producing bacteria are often multi-drug or even pan-drug resistant. Infections caused by such pathogens are difficult or sometimes impossible to treat. In this grant proposal we will perform detailed microbiological, kinetics and structural characterization of the major class D carbapenemases of A. baumannii. These enzymes are widely distributed in clinical A. baumannii isolated and have elevated this pathogen to the category of most deadly and difficult to treat, with mortality rates often exceeding 30-50%. We will elucidate the mechanism of carbapenemase activity of A. baumannii CHDLs and evaluate the evolutionary potential of these class D enzymes to further enhance their catalytic efficiency against carbapenems, rendering this important class of antibiotics obsolete for treatment of infections caused by this bacterial pathogen. Finally, we will design and test inhibitors of class D carbapenemases that would restore clinical utility of carbapenem antibiotic for combating deadly A. baumannii infections.