Identification and Characterization of Novel Antimicrobial Adjunctives to Restore Susceptibility to Carbapenem Resistant Enterobacteriaceae

项目摘要 细菌中的抗生素耐药性正在损害我们治疗感染的能力。令人担忧的是 肠杆菌科成员中的碳青霉烯类耐药性（所谓的碳青霉烯类耐药性 肠杆菌科（Enterobacteriaceae）或CRE），如肺炎克雷伯氏菌（Klebsiella pneumoniae）和肠杆菌属（Enterobacter spp.）因此，碳青霉烯类 是对抗多重耐药病原体的最后手段抗生素。收购广泛运作的 破坏这些药物的酶使得CRE的治疗充其量是有问题的。替代治疗 要么不存在要么毒性很强因此，CDC将CRE列为紧急威胁。有紧迫感 需要新的抗微生物剂和新的抗微生物靶标鉴定。重要的是，含有 相同的功能性碳青霉烯酶显示出对碳青霉烯类的敏感性的显著差异， 这表明碳青霉烯耐药是多因素的。事实上，一些菌株在临床上仍然敏感， 在体外和体内。因此，我们假设可以发现新的抗微生物剂， 导致耐药性的因素，从而恢复碳青霉烯类在非敏感菌株中的疗效。 因此，该提案将使用全面的高通量筛选（HTS）测定来鉴定新的 直接抑制CRE和/或使CRE对碳青霉烯类敏感的化合物。以下 鉴定，我们的目标是表征这些新化合物的作用机制，并深入了解 碳青霉烯耐药机制和CRE抗菌作用。长期目标是利用这个 知识，以开发新的有效的治疗CRE。

Project Summary Antibiotic resistance in bacteria is compromising our ability to treat infection. Of alarming concern is emerging carbapenem resistance amongst members of the Enterobacteriaceae (so called carbapenem-resistant Enterobacteriaceae or CRE) such as Klebsiella pneumoniae and Enterobacter spp. Heretofore, carbapenems were the class of antibiotics of last resort against multidrug-resistant pathogens. Acquisition of broadly acting enzymes that destroy these drugs has made treatment of CRE problematic at best. Alternative treatments are either absent or highly toxic. Accordingly, the CDC has classified CRE as an urgent threat. There is pressing need for novel antimicrobials and new antimicrobial target identification. Importantly, bacteria containing the same functional carbapenemase enzymes show marked differences in susceptibility to carbapenems, suggesting that carbapenem resistance is multi-factorial. In fact, some strains remain clinically susceptible both in vitro and in vivo. We therefore hypothesize that novel adjunctive antimicrobials can be found that modulate factors contributing to resistance and thereby restore the efficacy of carbapenems in non-susceptible strains. Therefore, this proposal will use a comprehensive, high-throughput screening (HTS) assay to identify novel compounds that either directly inhibit CRE and/or render CRE susceptible to carbapenems. Following identification, we aim to characterize the mechanism of action of these novel compounds and gain insight into mechanisms of carbapenem resistance and CRE antimicrobial effect. The long-term goal is to use this knowledge to develop novel effective therapies for CRE.