Resistance to Carbapenem Antibiotics in Acinetobacter baumannii

 描述(由申请人提供)：？-Lactam抗生素是最大的和临床上使用最多的抗菌剂家族。在革兰氏阴性菌中存在着一种能够破坏伯内酰胺类抗生素的酶，这是一个严重的临床问题。这些酶的一个子集，碳青霉烯酶，能强烈地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。具有碳青霉烯酶活性的酶在所有四种分子类(A、B、C和D类)中都被鉴定出来。D类碳青霉烯酶广泛分布在对其他抗生素类耐药的不动杆菌和肠杆菌科分离株中，这些 产生碳青霉烯酶的细菌往往是多药耐药，甚至泛耐药。由这种病原体引起的感染很难甚至有时是不可能治疗的。在这项拨款提案中，我们将对鲍曼不动杆菌主要的D类碳青霉烯酶进行详细的微生物学、动力学和结构表征。这些酶在临床分离的鲍曼不动杆菌中广泛分布，并已使这种病原体上升到最致命和最难治疗的类别，死亡率往往超过30%-50%。我们将阐明鲍曼不动杆菌碳青霉烯酶活性的机制，并评估这些D类酶的进化潜力，以进一步提高它们对碳青霉烯类抗生素的催化效率，使这一重要类别的抗生素被淘汰，用于治疗这种细菌病原体引起的感染。最后，我们将设计和测试D类碳青霉烯酶抑制剂，以恢复碳青霉烯类抗生素的临床用途，以对抗致命的鲍曼不动杆菌感染。

 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.