Genes of unknown function impacting antimicrobial resistance in enterococci

项目总结 抗生素耐药性的持续和不可避免的出现需要强有力和持续的 努力从根本上确定创新抗菌疗法的新目标和战略。 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菌部分原因是他们对常用药物的内在抗药性 针对细菌细胞膜的抗生素，如头孢菌素。然而，许多问题 关于肠球菌对头孢菌素耐药的遗传和生化基础仍然存在。在……里面 初步研究我们发现了两个编码“保守假说”的广泛保守的基因。 调节内源性肠球菌的未知功能蛋白质(称为IreB和IREC) 头孢菌素耐药。IreB是头孢菌素耐药的负调控因子，而IREC 增加抵抗力。然而，IreB和IREC影响头孢菌素的机制 阻力是未知的，几乎没有线索可以指导假说的发展来解释 他们的角色。这里提出的研究旨在阐明对IreB和IreB的作用的新见解 IREC在推动肠球菌头孢菌素耐药性的生物学过程中的作用。为此，我们将使用 识别影响头孢菌素的细胞因素的无偏全基因组遗传方法 与IreB和IREC合作进行抵抗。通过这样做，这里提出的研究将提供新的 对驱动肠球菌关键抗生素耐药性的基本生物学过程的洞察 并可能为旨在削弱肠球菌抗生素的创新疗法定义新的目标 抵抗。

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.