Mechanobiology of Neisseria Microcolonies

奈瑟菌微菌落的机械生物学

• 批准号: 8742377
• 负责人: Nicolas Biais
• 金额: $ 15.7万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742377
• 关键词: Address; Adhesions; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Architecture; Attention; Bacteria; Behavior; Biological Models; Cell Differentiation process; Cell Maturation; Cell-Cell Adhesion; Cells; Cellular biology; Cephalosporin Resistance; Cephalosporins; Chemicals; Communities; Complex; Cues; DNA; Data; Development; Diffusion; Disease; Drug resistance; Environment; Eukaryotic Cell; Event; Fiber; Foundations; Funding Opportunities; Gene Expression; Genes; Gonorrhea; Health; Human; Indium; Infection; International; Laboratories; Lead; Life; Microbial Biofilms; Neisseria; Neisseria gonorrhoeae; Nutrient; Pharmaceutical Preparations; Physiology; Pilot Projects; Pilum; Play; Process; Resolution; Resort; Role; Sexually Transmitted Diseases; Shapes; Signal Transduction; Staging; System; Testing; Time; United States National Institutes of Health; Work; arm; base; biological systems; biophysical properties; cancer cell; cell motility; fighting; human disease; innovation; pathogen; public health relevance; resistance allele; resistant strain; uptake; weapons

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae (Ng) is the etiologic agent of gonorrhea. With over 100 million annual cases worldwide, gonorrhea is one of the most common sexually transmitted diseases. In recent years, an alarming increase in antibiotic resistance among Neisseria gonorrhoeae strains has been a cause for great concern among all national and international health agencies. The current emergence of cephalosporin-resistant strains (so far cephalosporins are our last resort antibiotic treatment for gonorrhea) around the world emphasizes the need for both new treatments for gonorrhea, as well as a better understanding of the basic mechanisms behind antibiotic resistance. As with many other bacteria, Ng bacteria are rarely found as single cells. Instead they are first found in small clusters or microcolonies of a few tens to a few thousands bacteria and then in fully formed biofilms of up to millions of cells. Bacteria within biofilms are more resistant to antibiotic treatment than their free-living counterparts. Biofilms also play a major role in pathogen colonization and disease. While much progress has been made in understanding the architecture of the mature biofilm, the process by which biofilms develop remains less well understood. Understanding the early stages of biofilm development may lead to new therapies and treatments of important human diseases. Similarly to what has been shown between human cells, we postulate that the impact of physical forces is crucial in the formation and architecture of Ng microcolonies, the precursors of Ng biofilms. A key element in the formation of Ng microcolonies is the Type IV pilus (Tfp). Tfp are retractable bacterial fibers involved in many aspects of Ng physiology including motility, adhesion, infection, DNA uptake and biofilm formation. We have shown that the retraction of Tfp from Ng microcolonies can exert forces in the nanoNewton range (approximately 100,000 times the bodyweight of a single bacteria) and that these forces are capable of triggering signaling events in human cells. The objective of this study is to discover how the extreme forces of Tfp retraction shape Ng microcolony formation and the behavior of Ng bacteria within these communities. We will obtain this objective by pursuing three aims: identify how Tfp retraction forces shape microcolonies, determine the role of Tfp retraction forces in the initial steps of biofilm differentiation, and determine the role ofTfp retraction forces in the resistance to antibiotics and the spreading of antibiotic resistance. This work is of particular significance as it addresses a largely unknown and important stage of biofilm development. The findings here will lay the groundwork for future research on an important topic of human health. The proposed project is innovative as it will, for the first time, assess the role of physical forces in the formation and function of Ng microcolonies and achieve this at the single cell level.

描述（由申请人提供）：淋病奈瑟氏菌（NG）是淋病的病因学药。淋病在全球范围内拥有超过1亿例病例，是最常见的性传播疾病之一。近年来，在所有国家和国际卫生机构中，淋病菌株中抗生素耐药性的增加令人震惊。世界各地的抗淋病菌株的当前出现（到目前为止，头孢菌素是我们对淋病的最后度假抗生素治疗），这强调了对淋病的新治疗的需求，以及对抗生素耐药性背后基本机制的更好理解。与许多其他细菌一样，NG细菌很少被发现为单细胞。取而代之的是，它们首先是在几十至数千种细菌的小簇或微菌落中发现的，然后在多达数百万个细胞的完全形成的生物膜中发现。比其自由运动对应物，生物膜内的细菌对抗生素治疗具有更大的抵抗力。生物膜在病原体定植和疾病中也起着重要作用。尽管在理解成熟生物膜的结构方面取得了很大进展，但生物膜发展的过程仍然不太了解。了解生物膜发展的早期阶段可能会导致重要人类疾病的新疗法和治疗方法。与人类细胞之间显示的相似，我们假设物理力的影响对于NG微菌落的形成和结构至关重要，NG微菌落是NG生物膜的前体。 NG微菌落形成的关键要素是IV型菌毛（TFP）。 TFP是参与NG生理学许多方面的可伸缩细菌纤维，包括运动，粘附，感染，DNA摄取和生物膜形成。我们已经表明，从NG微菌落中缩回TFP可以在纳米沃顿范围内施加力（大约是单个细菌体重的100,000倍），并且这些力能够触发人类细胞中的信号传导事件。这项研究的目的是发现TFP回缩的极端力如何形状NG微菌株形成和NG细菌在这些群落中的行为。我们将通过追求三个目标来获得这一目标：确定TFP回收力如何塑造微菌落，确定TFP回收力在生物膜分化的初始步骤中的作用，并确定TFP回收力在抗生素抗性中的作用以及抗生素耐药性的传播。这 工作非常重要，因为它解决了生物膜开发的一个未知阶段和重要阶段。这里的发现将为未来关于人类健康的重要主题的研究奠定基础。拟议的项目是创新的，这是第一次 评估物理力在NG微菌落的形成和功能中的作用，并在单细胞水平上实现这一目标。