Engineering microbial social interactions: Towards new anti-biofilm therapies

工程微生物社会相互作用：迈向新的抗生物膜疗法

• 批准号: 9014932
• 负责人: Joao Xavier
• 金额: $ 15.28万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014932
• 关键词: 3-Dimensional; Antibiotic Resistance; Antibiotics; Award; Bacteria; Bacterial Infections; Cell Communication; Cells; Cellular biology; Clinical; Communities; Computing Methodologies; Drug usage; Engineering; Evolution; Face; Genes; Genetic; Goals; Human; Infection; Intervention; Lead; Life; Lung; Measures; Microbial Biofilms; Microbiology; Modeling; Molecular; Molecular Biology; Organism; Pathogenesis; Play; Population; Pseudomonas aeruginosa; Regulation; Regulatory Pathway; Reporter; Research; Resistance; Role; Shapes; Social Interaction; Solutions; Structure; System; Systems Biology; Testing; Time; Virulence; Virulent; abstracting; cystic fibrosis patients; design; fighting; microbial; next generation; pathogen; pathogenic bacteria; pressure; public health relevance; quorum sensing; response; rhamnolipid; social; targeted treatment; theories; treatment strategy

DESCRIPTION (Provided by the applicant) Abstract: Antibiotic resistance is a mounting problem at the global scale that compromises the use of these drugs as our main defense against microbial infections. The antibiotics themselves act as a selective pressure for resistance, and the present solution of developing new antibiotic classes only delays the problem until new resistance emerges. My goal is to develop entirely new strategies to fight pathogenic bacteria by targeting the social interactions involved in pathogenesis. The goal is motivated by the realization that most pathogenic bacteria are not isolated organisms, but rather live in multicellular communities called biofilms where cell-cell interactions are essential. Our recent applications of social evolutionary theory to microbiology have already shown that biofilm formation, quorum sensing and virulent secretions are highly dependent on interactions among cells and that the fate of cooperative interactions is challenged by the presence of competing strains. Therefore, I hypothesize that therapies that target social interactions can reduce the virulence of bacterial populations without creating strong selection for resistance. I will test this hypothesis in the bacterium Pseudomonas aeruginosa, an opportunistic human pathogen notorious for infecting the lungs of cystic fibrosis patients by forming antibiotic resistant biofilms. The formation of robust biofilms requires well-regulated secretion of rhamnolipid biosurfactants, which are self-produced dispersants that play a major role in shaping biofilm 3-D structure. I will investigate the conditions that lead to unregulated rhamnolipid secretion as potential strategies for self-induced biofilm dispersal. For the period of this award I will carry out three complementary research avenues that will combine quantitative-experimental and computational methods: (1) I will characterize the dynamic response of the quorum sensing regulation of biosurfactant secretion in P. aeruginosa. I will carry this out by selectively deleting genes in the regulatory pathway and measuring system response using reporter fusions. (2) I will develop the next generation of realistic 3-D computational biofilm models. I will apply these models to rationally design strategies that induce self-promoted biofilm dispersal. (3) I will quantify the networks of social interactions and test experimentally strategies that disperse biofilms by perturbing those interactions. These studies expand the applications of quantitative social evolution to molecular and cell biology, and will provide for the first time a systems view of microbial groups that integrates the dynamic observations of genetic and phenotypic diversity among cells with the importance of cellular cooperation. The project leverages my unique expertise at the interface of engineering, systems biology and evolution, and applies this expertise towards new therapies against microbial infection.

描述（由申请人提供） 摘要：抗生素耐药性在全球范围内是一个日益严重的问题，它损害了这些药物作为我们对抗微生物感染的主要防御手段的使用。抗生素本身作为耐药性的选择性压力，目前开发新抗生素类别的解决方案只能推迟问题，直到新的耐药性出现。我的目标是开发全新的策略，通过针对致病过程中涉及的社会互动来对抗病原菌。这一目标的动机是认识到大多数病原菌不是孤立的生物体，而是生活在称为生物膜的多细胞群落中，其中细胞间的相互作用是必不可少的。我们最近的应用程序的社会进化理论的微生物学已经表明，生物膜的形成，群体感应和有毒的分泌物是高度依赖于细胞之间的相互作用和合作的相互作用的命运受到挑战的竞争菌株的存在。因此，我假设针对社会互动的疗法可以降低细菌群体的毒力，而不会产生强烈的耐药性选择。我将在铜绿假单胞菌中检验这一假设，铜绿假单胞菌是一种机会性人类病原体，因通过形成抗生素耐药性生物膜感染囊性纤维化患者的肺部而臭名昭著。坚固的生物膜的形成需要调节良好的鼠李糖脂生物表面活性剂的分泌，鼠李糖脂生物表面活性剂是在形成生物膜3-D结构中发挥主要作用的自产分散剂。我将调查的条件下，导致不受管制的鼠李糖脂分泌作为潜在的战略自我诱导的生物膜分散。在此期间，我将开展三个互补的研究途径，将结合联合收割机定量实验和计算方法：（1）我将表征的动态响应的聚量感应调节铜绿假单胞菌的生物表面活性剂分泌。我将通过选择性地删除调控途径中的基因并使用报告融合来测量系统反应来实现这一点。(2)我将开发下一代逼真的三维生物膜计算模型。我将应用这些模型来合理设计策略，诱导自我促进的生物膜扩散。(3)我将量化社会互动的网络，并通过实验测试通过干扰这些互动来分散生物膜的策略。这些研究扩展了定量社会进化在分子和细胞生物学中的应用，并将首次提供微生物群体的系统观点，该观点将细胞间遗传和表型多样性的动态观察与细胞合作的重要性相结合。该项目利用了我在工程，系统生物学和进化界面方面的独特专业知识，并将这种专业知识应用于对抗微生物感染的新疗法。