Physiological responses to cell wall-active antibiotics in a Gram-positive bacterium

项目摘要 ! 抑制细胞壁合成的抗生素是控制细菌病原体的重要策略。这些 分子阻止肽聚糖球囊的扩张，导致细胞内容物的积累 而不伴随生长，最终导致细胞溶解。最近有报道称，一些... 阳性细菌对细胞壁活性抗生素的反应是刺激核苷酸的产生， 信使（p）ppGpp。由于这种分子可以抑制许多细胞过程，（p）抗生素中的ppGpp合成 经处理的细胞减少了总体生物合成，从而潜在地减少了与细胞的潜在致死不相容性。 细胞内容物持续积累并抑制细胞生长。这项提议旨在了解 这个机制的几个方面。首先，（p）ppGpp如何特异性地抑制细胞质生物合成 对细胞壁活性抗生素的反应第二，如何检测细胞壁活性抗生素-什么是 导致（p）ppGpp合成激活的信号转导级联？最后，如果这种自我平衡 在细胞壁活性抗生素的存在下，这种机制有助于生存，干扰这种机制 应该会使细菌对这些化合物更加敏感。因此，我们将利用在 研究这些问题，以确定干扰这一机制的分子，并确定它们是否改变了 细菌对细胞壁活性抗生素的敏感性。 !

Project Summary ! Antibiotics that inhibit cell wall synthesis serve as an important strategy to control bacterial pathogens. These molecules prevent expansion of the peptidoglycan sacculus, resulting in the accumulation of cellular contents without associated growth, ultimately leading to cellular lysis. Recently it has been reported that some Gram- positive bacteria respond to cell wall-active antibiotics by stimulating the production of the nucleotide second messenger (p)ppGpp. Since this molecule can inhibit many cellular processes, (p)ppGpp synthesis in antibiotic treated cells reduces overall biosynthesis and thereby potentially lessen the potentially lethal incompatibility of continued accumulation of cellular content and inhibited cell growth. This proposal is aimed at understanding several aspects of this mechanism. First, how does (p)ppGpp specifically act to inhibit cytoplasmic biosynthesis in response to cell wall active antibiotics? And second, how are cell-wall active antibiotics detected – what is the signal transduction cascade leading to the activation of (p)ppGpp synthesis? Finally, if this homeostatic mechanism facilitates survival in the presence of cell wall-active antibiotics, interference with this mechanism should make the bacteria more sensitive to these compounds. We will therefore use insights gained in investigating these questions to identify molecules that interfere with this mechanism and determine if they alter the sensitivity of the bacteria to cell wall-active antibiotics. !