Studies on the biological mechanisms of antibiotics

描述（由申请人提供）：革兰氏阳性和革兰氏阴性病原体引起的抗生素耐药细菌感染对人类健康构成严重威胁。耐药性正在增加，而对新抗生素和可能的新靶点的研究却滞后。革兰氏阳性和革兰氏阴性细菌都被一种交联的碳水化合物聚合物——肽聚糖所包围，这种聚合物在所有细菌中都是保守的。这种聚合物对细菌的生存至关重要，因为它能稳定细胞膜，抵抗高内部渗透压。肽聚糖的生物合成是抗生素的主要靶点，因为干扰这一过程会导致细胞裂解。本研究旨在了解万古霉素、青霉素和莫诺霉素的作用机制，这三种重要的抗生素代表了三种抑制肽聚糖合成的抗生素。为了了解这些药物的生物学机制，将采用一个综合程序，包括合成有机化学、生化和微生物分析、结构研究和细菌遗传学。更好地了解这些药物如何杀死可能会导致治疗策略，以改善其活性谱，使其更有效地杀死耐药微生物。由于这些化合物针对细菌的基本代谢过程，因此更好地了解这一过程也可能导致新的抗生素靶点或策略。

DESCRIPTION (provided by applicant): Antibiotic resistant bacterial infections caused by both Gram-positive and Gram-negative pathogens pose a serious threat to human health. Resistance is increasing while research into new antibiotics and possible new targets is lagging. Both Gram-positive and Gram-negative bacteria are surrounded by a cross-linked carbohydrate polymer, peptidoglycan, which is conserved in all bacteria. This polymer is essential for bacterial survival because it stabilizes the cell membrane against high internal osmotic pressures. Peptidoglycan biosynthesis is a major target for antibiotics because interfering with this process leads to cell lysis. This research is directed towards understanding the mechanisms of action of vancomycin, penicillin, and moenomycin, important antibiotics that represent three classes of antibiotics that inhibit peptidoglycan synthesis. To understand the biological mechanisms of these drugs, an integrated program involving synthetic organic chemistry, biochemical and microbiological assays, structural studies, and bacterial genetics will be employed. A better understanding of how these drugs kill might lead to therapeutic strategies to improve their spectrum of activity and make them more effective at killing resistant microorganisms. Since these compounds target a fundamental metabolic process in bacteria, a better understanding of this process could lead to new antibiotic targets or strategies as well. PUBLIC HEALTH RELEVANCE: Resistance to common antibiotics poses a serious threat to public health. The research proposed here is directed towards understanding the mechanism of action of three classes of antibiotics that inhibit bacterial cell wall synthesis. A better understanding of how these drugs kill might lead to therapeutic strategies to improve their spectrum of activity and make them more effective at killing resistant microorganisms.