Microbial Ecology-Guided Discovery of Antibacterial Drugs

项目概要/摘要 多重耐药细菌对健康的威胁日益严重。大多数新型抗菌剂都是天然产物 由细菌或其合成衍生物制成。这是因为，随着进化时间的推移，细菌获得了 合成小分子的能力，这些小分子非常选择性地针对其他细菌的基本过程。一 识别对人相对无毒的良好抗菌剂的问题是早期药物 在进入药物开发阶段之前，发现分析无法确定化合物是否真正具有选择性 过程。从环境中随机培养的细菌没有理由产生化学物质 它们对人类是良性的，但对竞争细菌却是致命的。寻找这些化合物，或改进现有的 化合物要尽量减少毒性并提高抗菌活性，需要大量投资。在这里，我们 提议检查与动物生理学相容的共生细菌，以及其进化 有利于选择性抗菌剂的生产。这些细菌在动物宿主体内富集，其中 他们生产数百甚至数千种小分子天然产品。主要生态之一 共生细菌的作用很可能是清除宿主中的其他细菌。概念验证实验 证明细菌产生的无毒化合物非常有选择性地针对人类病原体， 包括一些感染人类的最致命的细菌病原体。在这个程序中，我们将优化 通过了解其作用机制并通过 通过化学合成进一步研究和改进其现有特性。此外，我们将 继续识别和表征以前未知的有前途的新型抗菌剂 科学。我们的长期目标是提供新的抗菌药物管道来对抗多种药物 阻力。

Project Summary/Abstract Multidrug-resistant bacteria are an increasing health threat. Most new antibacterial agents are natural products that are made by bacteria, or their synthetic derivatives. This is because, over evolutionary time, bacteria gain the ability to synthesize small molecules that very selectively target essential processes in other bacteria. One problem in identifying good antibacterial agents that are relatively nontoxic to people is that early drug discovery assays cannot determine whether compounds are truly selective until well into the drug development process. There is no reason that randomly cultivated bacteria from the environment would produce chemicals that are benign in humans, yet lethal to competing bacteria. Finding those compounds, or improving existing compounds to minimize toxicity and improve antibacterial activity, requires a significant investment. Here, we propose to examine symbiotic bacteria that are compatible with animal physiology, and for which evolution favors the production of selective antibacterial agents. The bacteria are enriched within animal hosts, where they produce hundreds or perhaps thousands of small molecule natural products. One of the main ecological roles of the symbiotic bacteria is likely to clear other bacteria from the host. Proof-of-concept experiments demonstrate that the bacteria produce nontoxic compounds that very selectively target human pathogens, including some of the most lethal bacterial pathogens that infect humans. In this program, we will optimize identified, chemically novel antibacterial compounds by understanding their mechanisms of action and by investigating and improving their existing properties further through chemical synthesis. Further, we will continue to identify and characterize promising new antibacterial agents that are previously unknown to science. Our long-term goal is to provide a novel pipeline of new antibacterial agents to combat multidrug resistance.