Does growth efficiency determine the inoculum effect?

项目摘要/摘要 每年有280万美国人感染抗药性细菌。这导致死亡人数增加， 医院费用。此外，正在开发的新抗生素很少。目前迫切需要延长 通过了解细菌如何耐受抗生素治疗来了解现有抗生素的有用性。其中一种方法是 细菌对抗生素的耐受性是接种效应(IE)，其中细菌种群的初始密度 确定杀死种群所需的抗生素浓度：具有更高 密度将需要更多的抗生素才能杀死。在几乎所有的细菌和抗生素中都观察到了IE，在 临床环境。令人惊讶的是，我们目前还没有减少IE的治疗方法，IE会增加 治疗感染的能力。最近发现，细菌的代谢率可以决定细菌的 抗生素的有效性。较高的代谢率减少了杀死一个种群所需的抗生素用量 细菌的数量。这一发现在IE的背景下特别相关，因为细菌密度、新陈代谢和生长 是相互关联的。高密度种群在耗尽食物来源之前有一段短暂的增长期。 这一小的生长窗口导致了整体的低代谢率。密度较低的种群有更长的 在耗尽它们的食物来源之前，它们需要一段生长期。这一漫长的增长期导致了整体新陈代谢的高度 费率。因此，由于其整体较高的代谢率，低密度的种群需要较少的抗生素来 相对于高密度的种群来说，杀戮。生长速度和新陈代谢之间的这种关系可以是 被描述为增长效率。增长效率的变化可能会决定IE，但我们有 还没有研究过这个。这是一个需要解决的重要问题，因为人们对使用代谢物的兴趣越来越大。 辅助剂配合抗生素治疗，以提高抗生素疗效。然而，在不知道新陈代谢是如何发生的情况下 生长效率，影响IE，我们有可能增强细菌对抗生素的耐受能力，这将使情况复杂化 感染。本研究的目的是考察增长效率是如何决定IE的。这将对我们有帮助 实现我们改变细菌新陈代谢的长期目标，使细菌更容易使用抗生素杀死。至 为了达到我们的目标，我们将首先研究生长效率如何决定铜绿假单胞菌的IE和 金黄色葡萄球菌，目标是确定可以减少甚至消除IE的生长条件。下一首, 我们将发现是什么基因和生化途径决定了生长效率和IE的发育 一种分子机制。我们的工作可能会导致新抗生素的开发，以减少或消除IE。 我们将使用一系列实验来测量生长、新陈代谢和抗生素的杀伤力。 细菌。我们将把这些实验与数学建模、计算机模拟和 生物信息学。拟议的工作将包括研究生和本科生参与跨学科研究。 重点是了解抗生素耐受性。

Project Summary/Abstract 2.8 million Americans are infected with antibiotic resistant bacteria annually. This leads to increased deaths and hospital costs. Moreover, there are few new antibiotics being developed. There is a dire need to extend the usefulness of existing antibiotics by understanding how bacteria tolerate antibiotic treatment. One way that bacteria tolerate antibiotics is the inoculum effect (IE), where the initial density of a bacterial population determines the concentration of antibiotic required to kill the population: a population of bacteria with a higher density will require more antibiotics to kill. IE has been observed in nearly all bacteria and antibiotics, and in the clinical setting. Surprisingly, we currently do not have treatment approaches that reduce IE, which would increase the ability to treat infections. It has been recently discovered that bacterial metabolic rate can determine the effectiveness of antibiotics. A higher metabolic rate reduces the amount of antibiotic required to kill a population of bacteria. This finding is particularly relevant in the context of IE, as bacterial density, metabolism, and growth are interrelated. Highly dense populations have a short period of growth before they exhaust their food source. This small window of growth leads to an overall low metabolic rate. Lower density populations have a longer period of growth before exhausting their food source. This long period of growth leads to an overall high metabolic rate. Thus, due its overall higher metabolic rate, the population with low density would require less antibiotic to kill relative to the high density population. This relationship between growth rate and metabolism can be described as growth efficiency. It is possible that changes in growth efficiency can determine IE, but we have not yet studied this. This is an important question to address as there is growing interest in using metabolite adjuvants with antibiotic treatment to increase antibiotic efficacy. However, without knowing how metabolism, or growth efficiency, affect IE, we risk enhancing the ability of bacteria tolerate antibiotics, which will complicate infections. The goal of this research is to investigate how growth efficiency determines IE. This will help us achieve our long term goal of altering bacterial metabolism to make bacteria easier to kill using antibiotics. To address our goal, we will first examine how growth efficiency determines IE in Pseudomonas aeruginosa and Staphylococcus aureus with a goal of determining growth conditions that can reduce, or even eliminate, IE. Next, we will discover what genes and biochemical pathways determine growth efficiency and IE towards developing a molecular mechanism. Our work may lead to the development of new antibiotics that reduce, or eliminate, IE. We will use a combination of experiments that measure growth, metabolism and the ability of antibiotics to kill bacteria. We will couple these experiments with mathematical modeling, computer simulations and bioinformatics. The proposed work will involve graduate and undergraduate students in interdisciplinary research with a focus on understanding antibiotic tolerance.