Microbial Ecology-Guided Discovery of Antibacterial Drugs

项目概要/摘要 多重耐药细菌是一个日益严重的健康威胁。大多数新的抗菌剂是天然产物 是由细菌或其合成衍生物制造的。这是因为，随着进化时间的推移， 合成小分子的能力，这些小分子非常有选择性地针对其他细菌的基本过程。一 在鉴定对人相对无毒的好的抗菌剂方面的问题是， 直到药物开发的很好阶段，发现试验才能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会产生化学物质 对人类无害，但对竞争细菌致命。找到这些化合物，或改善现有的 为了使毒性最小化并提高抗菌活性，需要大量的投资。这里我们 我建议研究与动物生理学相容的共生细菌， 有利于选择性抗菌剂的生产。细菌在动物宿主体内富集， 它们产生成百上千的小分子天然产物。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。在这个项目中，我们将优化 通过了解其作用机制， 研究并通过化学合成进一步改善其现有性能。此外，我们将 继续鉴定和表征以前未知的有前途的新抗菌剂， 科学我们的长期目标是提供一种新型抗菌剂的新管道，以对抗多药耐药。 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.