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。这层膜上的蛋白质起着选择性屏障的作用，阻挡有害物质（如药物或病毒），并传递关键的营养物质。OM蛋白的表达受环境调节：温度、酸度和抗生素暴露的变化会导致OM蛋白组成发生巨大变化。传统上，蛋白质表达只在大量细菌中进行研究，测量平均值。人们对人群中OM的异质性知之甚少。事实上，非遗传变异是存在的，并导致了细菌对抗生素治疗反应的行为差异。非遗传变异作为一种对冲，牺牲了一些细胞在当前条件下的优化，以便这些细胞在条件发生变化时再生群体的能力。行为变化的原因尚不清楚，但已确定的OM组成与抗生素耐药性之间的联系表明外膜不均一性的作用。本研究旨在(1)量化细胞间OM表达的变异，(2)测试群体可能产生这种变异的几种可能机制，以及(3)测量这种自然变异在包括抗生素治疗在内的不断变化的条件下对细菌存活的贡献。公共卫生相关性：传染病的威胁目前是全世界过早死亡的主要原因[1]，而抗菌素耐药性的频率和严重程度日益增加以及抗生素治疗失败率的上升，使这一威胁更加严重[1]。为了减少细菌感染对人类生命造成的日益严重的伤害，首先有必要了解细菌在抗生素治疗的挑战下是如何生存的。本研究的目的是量化细菌在面对抗生素胁迫时对生存和适应性的非遗传多样性的贡献。1. 《全球疾病负担：2004年最新情况》。编辑：世界卫生组织；2008. 2. 张晓明，张晓明，张晓明，张晓明，等。美国传染病学会抗微生物药物可及性工作组的研究进展。中华临床感染杂志，2006,42(2):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.