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：抗生素耐药性是全球范围内一个日益严重的问题，影响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。抗生素本身对耐药性产生选择性压力，而目前开发新抗生素类别的解决方案只能推迟问题的解决，直到出现新的耐药性。我的目标是通过针对发病机制中涉及的社会相互作用来开发对抗病原菌的全新策略。这一目标的动机是认识到大多数病原细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，其中细胞与细胞的相互作用至关重要。我们最近将社会进化理论应用于微生物学已经表明，生物膜形成、群体感应和有毒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的挑战。因此，我假设针对社交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，因形成抗生素抗性生物膜而感染囊性纤维化患者的肺部而臭名昭著。坚固生物膜的形成需要鼠李糖脂生物表面活性剂的良好分泌，鼠李糖脂生物表面活性剂是自行产生的分散剂，在塑造生物膜 3-D 结构中发挥着重要作用。我将研究导致鼠李糖脂分泌不受调节的条件，作为自诱导生物膜分散的潜在策略。在该奖项期间，我将开展三个互补的研究途径，将定量实验和计算方法结合起来：（1）我将描述铜绿假单胞菌中生物表面活性剂分泌的群体感应调节的动态响应。我将通过选择性删除调控途径中的基因并使用报告基因融合测量系统响应来实现这一点。 (2) 我将开发下一代逼真的 3D 计算生物膜模型。我将应用这些模型来合理设计诱导自我促进生物膜扩散的策略。 (3) 我将量化社交互动网络，并通过实验测试通过扰乱这些互动来分散生物膜的策略。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，并将首次提供微生物群体的系统视图，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结合起来。该项目利用了我在工程、系统生物学和进化方面的独特专业知识，并将这些专业知识应用于对抗微生物感染的新疗法。