Genes of unknown function impacting antimicrobial resistance in enterococci

影响肠球菌耐药性的未知功能基因

• 批准号: 9370219
• 负责人: CHRISTOPHER J KRISTICH
• 金额: $ 23.1万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-06 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370219
• 关键词: Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Automobile Driving; Bacterial Genes; Binding; Biochemical; Biological Process; Cell Wall; Cell physiology; Centers for Disease Control and Prevention (U.S.); Cephalosporin Resistance; Cephalosporins; Cytoplasmic Protein; DNA Binding Domain; Data; Development; Drug resistance; Enterococcus; Exhibits; Family; Foundations; Funding Mechanisms; Genes; Genetic; Genome; Healthcare; Hospitals; Impairment; Incidence; Infection; Intervention; Knowledge; Lead; Multi-Drug Resistance; Nosocomial Infections; Occupations; PAWR protein; Pathway interactions; Penicillin-Binding Proteins; Phenotype; Physiological; Proteins; Reporting; Research; Resistance; Ribonuclease H; Role; Substrate Specificity; Suppressor Mutations; Therapeutic; United States; Vancomycin resistant enterococcus; Work; antimicrobial; bacterial resistance; base; cell envelope; crosslink; design; genetic analysis; genetic approach; genome-wide; in vivo; innovation; insight; member; methicillin resistant Staphylococcus aureus; mutant; new therapeutic target; novel; novel therapeutics; pathogen; phosphoric diester hydrolase; prevent; programs; protein function; resistance factors; trait

PROJECT SUMMARY The continued and inevitable emergence of antibiotic resistance demands a vigorous and sustained effort to identify fundamentally new targets and strategies for innovative antimicrobial therapeutics. Antibiotic-resistant enterococci are major causes of hospital-acquired infections. Enterococci are successful hospital-acquired pathogens in part because of their intrinsic resistance to commonly used antibiotics that target the bacterial cell envelope, such as cephalosporins. However, many questions remain regarding the genetic and biochemical basis for cephalosporin resistance in enterococci. In preliminary studies we identified two widely conserved genes encoding “conserved hypothetical” proteins of unknown function (termed IreB and IreC) that modulate intrinsic enterococcal cephalosporin resistance. IreB acts as a negative regulator of cephalosporin resistance, while IreC promotes resistance. However, the mechanisms by which IreB and IreC influence cephalosporin resistance are unknown, and few clues are available to guide the development of hypotheses to explain their roles. The research proposed here is designed to elucidate new insights into the roles of IreB and IreC in the biological processes that drive enterococcal cephalosporin resistance. To do so, we will use unbiased, genome-wide genetic approaches to identify cellular factors that influence cephalosporin resistance in cooperation with IreB and IreC. By doing so, the research proposed here will provide new insights into the fundamental biological processes that drive key antibiotic resistance in enterococci and may define new targets for innovative therapeutics designed to impair enterococcal antibiotic resistance.

项目摘要 抗生素耐药性的持续和不可避免的出现需要充满活力和持久 努力确定创新抗菌疗法的新目标和策略。 耐药肠球菌是医院获得感染的主要原因。肠球菌是 成功医院获得的病原体部分是因为它们对常用的固有抗药性 靶向细菌细胞包膜的抗生素，例如头孢菌素。但是，很多问题 关于肠球菌中头孢菌素抵抗的遗传和生化基础。 初步研究，我们确定了两个广泛保守的基因，编码了“保守假设” 未知功能（称为IREB和IREC）的蛋白质调节固有的肠球菌 头孢菌素耐药性。 IREB充当头孢菌素耐药性的负调节剂，而IREC 促进阻力。但是，IREB和IREC影响头孢菌素的机制 阻力是未知的，很少有线索可指导假设的发展以解释 他们的角色。此处提出的研究旨在阐明对IREB和IREB角色的新见解 IREC在驱动肠肠球菌耐药性的生物过程中。为此，我们将使用 无偏见的全基因组遗传方法鉴定影响头孢菌素的细胞因子 与IREB和IREC合作的抵抗。通过这样做，这里提出的研究将提供新的 洞悉驱动肠球菌中关键抗生素耐药性的基本生物学过程 并可能定义了旨在损害肠肠抗生素的创新治疗剂的新目标 反抗。