Resistance to Carbapenem Antibiotics in Acinetobacter baumannii

鲍曼不动杆菌对碳青霉烯类抗生素的耐药性

• 批准号: 9887256
• 负责人: JOHN D BUYNAK
• 金额: $ 67.39万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887256
• 关键词: Acinetobacter baumannii; Affinity; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Applications Grants; Bacteria; Bacterial Antibiotic Resistance; Binding; Carbapenems; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Complex; Crystallization; Development; Disease; Drug resistance; Enzymes; Evaluation; Funding; Generations; Goals; Grant; Health; Healthcare; Human; Individual; Infection; Kinetics; Knowledge; Libraries; Mediating; Meropenem; Microbiology; Modification; Molecular Weight; Monobactams; Penetration; Penicillin-Binding Proteins; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Production; Research; Resistance; Resort; Risk; Roentgen Rays; Role; Structure; Testing; United States; VDAC1 gene; antibiotic efflux; antimicrobial; antimicrobial drug; beta-Lactam Resistance; beta-Lactamase; carbapenem resistance; carbapenemase; chemical stability; deacylation; design; efflux pump; enzyme activity; experimental study; healthcare-associated infections; improved; infection rate; inhibitor/antagonist; microorganism; mortality; mutant; novel; novel therapeutics; open data; pathogen; pathogenic bacteria; periplasm; resistance mechanism; scaffold; treatment choice; uptake

ABSTRACT Acinetobacter baumannii is listed by the CDC as a clinical pathogen that poses a serious antibiotic resistance threat in the United States. A. baumannii is resistant to antimicrobial agents of different classes, but the most troublesome is resistance to the last resort carbapenem antibiotics, which were the drugs of choice for treatment of infections caused by this microorganism. The major mechanism of resistance of A. baumannii to carbapenems is production of antibiotic-inactivating enzymes, carbapenem-hydrolyzing class D β-lactamases or CHDLs. In addition, sensitivity of carbapenem targets, bacterial penicillin-binding proteins (PBPs), rates of antibiotic penetration into the bacterial cell and/or their expulsion by efflux pumps can also contribute to resistance. Levels of resistance to carbapenem antibiotics reach up to 90% in some parts of the world, and mortality rates from infections caused by such bacteria are staggeringly high, up to 50%. Our long-term goal is to develop novel antibiotics for treatment of deadly A. baumannii infections. During the first cycle of funding for this grant proposal, we performed in-depth characterization of clinically important CHDLs and proposed the mechanism for their carbapenemase activity, which provides guidance for development of a new generation of carbapenems capable of inhibiting these enzymes. The continuation of this research will be a collaborative effort with Dr. John Buynak (co-PI) who developed dozens of novel atypically- modified carbapenem antibiotics. We used these antibiotics to test our proposed mechanism for deacylation and found three that inhibit the most prevalent A. baumannii CHDL, OXA-23, and possess superior activity (when compared to commercial carbapenems) against OXA-23-producing A. baumannii. Our proposed studies are aimed at in-depth characterization of these promising novel drugs. We will determine activity of our compounds against A. baumannii strains expressing major CHDLs and unveil kinetic and structural features responsible for their ability to inhibit these enzymes (Aim 1). We will evaluate interaction of our novel carbapenems with their targets, PBPs, and determine to what extent efflux pumps and porins influence bacterial resistance to these antibiotics (Aim 2). Finally, we will design and characterize several dozen novel carbapenem antibiotics with the aim to further improve their antimicrobial activity by enhancing their inhibitory potency against CHDLs, improving affinity for PBPs and increasing penetration rates and resistance to efflux (Aim 3).

摘要 鲍曼不动杆菌被CDC列为临床病原体，构成严重的抗生素 美国的抵抗威胁。A.鲍曼不动杆菌对不同种类的抗菌药物耐药 类，但最麻烦的是耐药性的最后手段碳青霉烯类抗生素，这是 治疗由这种微生物引起的感染的药物选择。的主要机制 抗A。鲍曼不动杆菌对碳青霉烯类的作用是产生抗生素失活酶， 碳青霉烯水解D类β-内酰胺酶或CHDL。此外，碳青霉烯的敏感性 目标，细菌青霉素结合蛋白（PBP），抗生素渗透到细菌细胞中的速率 和/或它们被外排泵排出也可导致抗性。抵抗水平 碳青霉烯类抗生素在世界某些地区高达90%， 由此类细菌引起的死亡率高得惊人，高达50%。我们的长期目标是开发新颖的 抗生素治疗致命的A.鲍曼不动杆菌感染。在该赠款的第一个供资周期内， 我们对临床上重要的CHDL进行了深入的表征，并提出了 其碳青霉烯酶活性的机制，这为开发新的 产生能够抑制这些酶的碳青霉烯类。这项研究的继续将 是一个合作的努力与博士约翰Buynak（共同PI）谁开发了几十个新的药物- 改良碳青霉烯类抗生素我们使用这些抗生素来测试我们提出的机制， 去酰化，并发现三个抑制最普遍的A。鲍曼不动杆菌CHDL、OXA-23，并具有 上级产OXA-23的A. 鲍曼不动杆菌。我们提出的研究旨在深入表征这些有前途的新的 毒品我们将测定我们的化合物对A的活性。鲍曼不动杆菌菌株主要表达 CHDL和揭示的动力学和结构特点，负责他们的能力，以抑制这些酶 (Aim 1）。我们将评估我们的新型碳青霉烯类与其靶点PBPs的相互作用，并确定 外排泵和孔蛋白在多大程度上影响细菌对这些抗生素的耐药性（目的2）。 最后，我们将设计和表征几十种新型碳青霉烯类抗生素，目的是 通过增强它们对CHDL的抑制效力进一步改善它们的抗微生物活性， 提高对PBPs的亲和力，增加渗透率和外排阻力（目标3）。