Genes of unknown function impacting antimicrobial resistance in enterococci

项目摘要 抗生素耐药性的持续和不可避免的出现需要一个强有力的和持续的 努力从根本上确定新的目标和创新的抗菌治疗策略。 耐药肠球菌是医院获得性感染的主要原因。肠球菌是 成功的医院获得性病原体，部分原因是它们对常用的 针对细菌细胞包膜的抗生素，如头孢菌素。然而，许多问题 关于肠球菌中头孢菌素耐药性的遗传和生化基础，在 初步研究，我们确定了两个广泛保守的基因编码“保守的假设” 功能未知的蛋白质（称为IreB和IreC），调节肠球菌内源性 头孢菌素耐药IreB作为头孢菌素耐药性的负调节剂，而IreC 促进抵抗。然而，IreB和IreC影响头孢菌素的机制 阻力是未知的，很少有线索可用于指导假说的发展，以解释 他们的角色这里提出的研究旨在阐明IreB和 IreC在驱动肠球菌头孢菌素耐药性的生物过程中的作用为此，我们将使用 无偏见的，全基因组遗传学方法，以确定影响头孢菌素的细胞因子 与IreB和IreC合作抵抗。通过这样做，这里提出的研究将提供新的 深入了解驱动肠球菌关键抗生素耐药性的基本生物学过程 并可能为旨在削弱肠球菌抗生素的创新疗法定义新的靶点 阻力

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.