Studies on the biological mechanisms of antibiotics

抗生素的生物学机制研究

• 批准号: 8111293
• 负责人: Daniel Kahne
• 金额: $ 63.29万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111293
• 关键词: Anabolism; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Bambermycins; Binding; Biochemical; Biological; Biological Assay; Carbohydrates; Cell Death; Cell Separation; Cell Wall; Cell membrane; Cells; Characteristics; Cytolysis; Drug Kinetics; Ensure; Enzymes; Evaluation; Funding; Gram-Negative Bacteria; Gram-Positive Bacteria; Health; Human; Lead; Length; Lipids; Mediating; Metabolism; Molecular; Monobactams; Organic Chemistry; Osmotic Pressure; Penicillin-Binding Proteins; Penicillins; Peptidoglycan; Peptidoglycan glycosyltransferase; Peptidyltransferase; Pharmaceutical Preparations; Polymers; Polysaccharides; Process; Property; Pseudomonas aeruginosa; Public Health; Recruitment Activity; Research; Resistance; Role; Route; Series; Therapeutic; Vancomycin; Vancomycin Resistance; analog; bacterial genetics; base; beta-Lactams; crosslink; daughter cell; drug mechanism; improved; killings; microorganism; moenomycin A; pathogen; phosphoglycerate; physical property; programs; public health relevance; research study; sensor; sugar

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.

描述（由申请方提供）：由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交联的碳水化合物聚合物肽聚糖包围，肽聚糖在所有细菌中都是保守的。这种聚合物对于细菌的生存是必不可少的，因为它可以稳定细胞膜以抵抗高的内部渗透压。肽聚糖生物合成是抗生素的主要靶标，因为干扰该过程会导致细胞裂解。本研究旨在了解万古霉素、青霉素和默诺霉素的作用机制，这些重要抗生素代表了三类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，将采用涉及合成有机化学，生物化学和微生物测定，结构研究和细菌遗传学的综合方案。更好地了解这些药物如何杀死可能导致治疗策略，以改善其活性谱，使其更有效地杀死耐药微生物。由于这些化合物靶向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。 公共卫生相关性：对常见抗生素的耐药性对公共卫生构成严重威胁。本文提出的研究旨在了解三类抑制细菌细胞壁合成的抗生素的作用机制。更好地了解这些药物如何杀死可能导致治疗策略，以改善其活性谱，使其更有效地杀死耐药微生物。