Outer membrane heterogeneity and adaptability in isogenic bacteria

描述（由申请人提供）：革兰氏阴性菌的外膜（OM）是其与外界的界面。这种膜中的蛋白质充当选择性屏障，阻止有害物质（如药物或病毒）并通过关键营养素。OM蛋白表达受环境调节：温度、酸度和抗生素暴露的变化导致OM蛋白组成发生显著变化。传统上，蛋白质表达仅在大量细菌中进行研究，测量大量细菌的平均值。很少有人知道OM异质性的人口。事实上，非遗传变异是存在的，并导致细菌对抗生素治疗反应的行为差异。非遗传变异起到了对冲的作用，牺牲了当前条件下某些细胞的优化，以换取这些细胞在条件发生变化时再生种群的能力。行为变异的原因尚不清楚，但OM组成和抗生素耐药性之间的联系表明外膜异质性的作用。这项研究的目的是（1）量化OM表达的细胞间变异，（2）测试种群可能产生这种变异的几种可能机制，（3）测量这种自然变异对细菌在变化条件下存活的贡献，包括抗生素治疗。公共卫生相关性：传染病的威胁目前是全球过早死亡的主要原因[1]，而抗生素耐药性的频率和严重程度增加以及抗生素治疗失败率的上升[2]则加剧了这一威胁。为了减少细菌感染对人类生命造成的日益严重的损失，首先需要了解细菌在受到抗生素治疗的挑战时如何生存。这项研究的目的是量化细菌中非遗传多样性对抗生素压力下生存和适应性的贡献。1.全球疾病负担：2004年最新情况。编辑：世界卫生组织; 2008年。2.塔尔博特GH，布拉德利J，爱德华兹JE，Jr.，吉尔伯特D，谢尔德M，巴特利特JG：坏虫子需要药物：美国传染病学会抗菌药物可用性工作组开发管道的最新情况。临床感染疾病2006，42：657-668。

DESCRIPTION (provided by applicant): The outer membrane (OM) of a Gram negative bacterium is its interface with the outside world. Proteins in this membrane act as selective barriers to block harmful substances (such as drugs or viruses) and pass critical nutrients. OM protein expression is environmentally regulated: shifts in temperature, acidity, and exposure to antibiotics cause dramatic changes in OM protein composition. Protein expression is traditionally only studied in bulk, measuring an average over large numbers of bacteria. Little is known about OM heterogeneity within the population. In fact, non-genetic variation is present and causes behavioral differences in the response of bacteria to antibiotic treatment. Non-genetic variation acts as a hedge, sacrificing the optimization of some cells under current conditions for the ability of these cells to regenerate the population in the event that conditions change. The causes of behavioral variation are unknown, but the established link between OM composition and antibiotic resistance suggests a role for outer membrane heterogeneity. This research aims to (1) quantify cell-to cell variation in OM expression, (2) test several possible mechanisms by which the population may generate this variation, and (3) measure the contribution of this natural variation to bacterial survival under changing conditions including antibiotic treatment. PUBLIC HEALTH RELEVANCE: The threat from infectious disease, currently the leading cause of premature death worldwide [1], is compounded by the increasing frequency and severity of antimicrobial resistance and rise in the rate of failure of antibiotic treatments [2]. In order to reduce the growing toll on human life taken by bacterial infections, it is first necessary to understand how bacteria survive when challenged by antibiotic treatment. The goal of this research is to quantify the contribution of non-genetic diversity in bacteria to survival and adaptability in the face of antibiotic stress. 1. The Global Burden of Disease: 2004 Update. Edited by: World Health Organization; 2008. 2. Talbot GH, Bradley J, Edwards JE, Jr., Gilbert D, Scheld M, Bartlett JG: Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 2006, 42:657-668.