Antibiotic Hypersusceptibility Mutations in Bacteria

描述（改编自申请人的摘要）： 细菌对抗生素的耐药性要求彻底改变现有的 抗菌治疗最有希望的方法之一是使用 抗生素增效剂，使细菌细胞过敏的化合物 抗生素。该项目的目标是鉴定多种新的分子 增效剂的目标。这将通过分离抗生素来实现 革兰氏阴性菌、不动杆菌和/或 大肠埃希菌这些突变将指定细菌蛋白质， 抑制可能增强抗生素抗微生物作用。 抗生素过敏性是一种很难选择的表型， 只有少数这样的突变是已知的。我们设计并测试了一种新的基因 用于选择过敏性突变的策略，称为SDR。 该策略的应用将识别多个突变， 细菌对β-内酰胺类（氨苄西林、头孢他啶、亚胺培南）的敏感性， 翻译抑制剂（红霉素、利奈唑胺、四环素和 氯霉素）和氟喹诺酮类抗生素（环丙沙星）。分子 这些最有趣的突变的潜在机制 将被分析。除了确定有希望的目标外， 该项目将有助于揭示新的方面的机制， 抗生素的作用和细菌生理学的新特征。

DESCRIPTION (Adapted from the Applicant's Abstract): The escalating problem of bacterial resistance to antibiotics calls for radical changes in the existing antibacterial therapies. One of the most promising approaches is the use of antibiotic potentiators, compounds that make bacterial cells hypersusceptible to antibiotics. The goal of the project is to identify multiple novel molecular targets for potentiators. This will be accomplished by isolating antibiotic hypersusceptibility mutations of Gram-negative bacteria, Acinetobacter and/or Escherichia coli. These mutations will specify bacterial proteins whose inhibition is likely to potentiate antimicrobial action of antibiotics. Antibiotic hypersusceptibility is a very difficult phenotype to select, and only few such mutations are known. We have designed and tested a novel genetic strategy for selection of hypersusceptibility mutations, termed SDR. Application of this strategy will identify multiple mutations increasing bacterial susceptibility to beta-lactams (ampicillin, ceftazidime, imipenem), translational inhibitors (erythromycin, linezolid, tetracycline, and chloramphenicol) and fluoroquinolone antibiotics (ciprofloxacin). The molecular mechanisms underlying the effects of the most interesting of these mutations will be analyzed. In addition to identifying promising targets for potentiators, the project will help unravel new aspects of the mechanism of action of antibiotics and new features of bacterial physiology.