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（申请人提供） 摘要：在全球范围内，抗生素耐药性是一个越来越多的问题，它损害了这些药物作为我们针对微生物感染的主要防御。抗生素本身是抗性的选择压力，目前开发新抗生素类别的解决方案只会延迟该问题，直到出现新的抗药性。我的目标是制定全新的策略，以针对发病机理涉及的社会互动来抵抗致病细菌。目的是由认识到大多数病原菌不是孤立生物的，而是生活在称为生物膜的多细胞群落中，其中细胞细胞相互作用是必不可少的。我们最近将社会进化理论在微生物学上的应用已经表明，生物膜形成，法定感应和有毒的分泌物高度依赖于细胞之间的相互作用，并且合作相互作用的命运受到竞争菌株的存在挑战。因此，我假设靶向社交相互作用的疗法可以减少细菌种群的毒力，而不会为抗药性提供强烈的选择。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的人类病原体，该病原体因通过形成抗生素耐药性生物膜来感染囊性纤维化患者的肺而臭名昭著。鲁棒生物膜的形成需要对鼠李糖脂生物表面活性剂进行良好调节的分泌，它们是自生产的分散剂，它们在塑造生物膜3-D结构中起主要作用。我将调查导致不受管制的鼠李糖尿脂分泌的条件，这是自我诱导的生物膜分散的潜在策略。在该奖项期间，我将进行三个互补的研究途径，这些途径将结合定量实验和计算方法：（1）我将表征铜绿铜分泌物铜绿病毒分泌的群体传感调节的动态响应。我将通过在调节途径中选择性删除基因并使用报告基因融合来测量系统响应来执行此操作。 （2）我将开发下一代现实的3-D计算生物膜模型。我将将这些模型应用于诱发自我促进的生物膜扩散的合理设计策略。 （3）我将量化通过扰动这些相互作用来分散生物膜的社交互动和实验策略的网络。这些研究将定量社会进化的应用扩展到分子和细胞生物学上，并将首次提供微生物基团的系统视图，这些系统将细胞之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，系统生物学和进化的界面上的独特专业知识，并将这种专业知识应用于针对微生物感染的新疗法。