Post-transcriptional regulation of biofilm formation S. aureus

描述(申请人提供)：金黄色葡萄球菌是院内血流感染最常见的原因之一，也是心内膜炎、骨髓炎和其他感染的重要原因。金黄色葡萄球菌对抗生素的耐药性是一个严重的临床问题，这种细菌在人体组织和插入的医疗设备(如导管)上形成生物膜的能力使其变得更加复杂。大多数金黄色葡萄球菌能够在适当的环境条件下形成一种表面相关的(3-1-6-连接的)N-乙酰-氨基葡萄糖(PNAG)聚合物，它具有两个重要的毒力功能：1.它是生物膜外聚合物基质的主要成分；2.它保护细菌在感染过程中不被吞噬。在感染过程中生物被膜的发展通常会导致细菌种群对抗菌素化疗无效，并可能成为复发感染的阴燃病灶。此外，对吞噬的抵抗力使细菌能够逃避免疫系统。因此，编码参与PNAG合成的四种蛋白Ica A、ICAD、ICab和ICac的细胞间粘附素(ICA)基因似乎在毒力中发挥关键作用也就不足为奇了。通过抑制耐药生物膜的形成，可以显著改善目前金黄色葡萄球菌感染的治疗方法。该项目的长期目标是表征PNAG加工和随后金黄色葡萄球菌生物膜形成的调节。对这一途径的彻底了解可能有助于确定抗生物被膜治疗剂与常规抗生素协同作用的靶点。这涉及2010年健康人与“传染病和新出现的抗菌素耐药性”作斗争的目标和目标14-20“医院获得性感染”。我们已经分离出一种与ICA转录本结合的RNA结合蛋白，它似乎可以延长RNA的半衰期并抑制翻译。这项拟议项目的近期目标是进一步表征这种RNA结合蛋白调控ICA表达和PNAG产生的转录后调控机制BV。简短的描述。金黄色葡萄球菌是一种重要的致病菌，可引起多种感染。金黄色葡萄球菌对抗生素的耐药性很常见，而且它能够形成被称为生物膜的粘附性、多糖包裹的群落，使问题变得更加复杂。本研究的目的是研究金黄色葡萄球菌生物膜形成的调控机制。了解生物被膜调节的机制可以导致开发与常规抗生素协同作用的抗生物被膜疗法。

DESCRIPTION (provided by applicant): Staphylococcus aureus is one of the most common causes of nosocomial bloodstream infections and is also an important cause of endocarditis, osteomyelitis, and other infections. Antibiotic resistance in S. aureus is a serious clinical problem that is compounded by the ability of the organism to form a biofilm on human tissues and inserted medical devices such as catheters. Most strains of S. aureus are able, under the appropriate environmental conditions, to elaborate a surface-associated (3-1-6-linked polymer of N-acetyl-glucosamine (PNAG) that serves two significant virulence functions: 1. it functions as the major constituent of the biofilm exo-polymeric matrix and 2. it protects the bacteria from phagocytosis during infection. The development of a biofilm during infection often results in a bacterial population that is refractory to antimicrobial chemotherapy and can act as a smoldering nidus for relapsing infection. In addition, resistance to phagocytosis enables the bacteria to evade the immune system. Therefore, it is not surprising that the intercellular adhesin (ica) locus, which encodes four proteins, Ica A, IcaD, IcaB, and IcaC, that are involved in PNAG synthesis, appears to play a critical role in virulence. Current therapeutic modalities for S. aureus infections could be significantly improved by inhibiting the formation of a resistant biofilm. The long-term objective of this project is to characterize the regulation of PNAG elaboration and subsequent biofilm formation bv S. aureus. A thorough understanding of this pathway could lead to the identification of targets for anti-biofilm therapeutic agents to act svnergisticallv with conventional antibiotics. This addresses the Healthy People 2010 goal of fighting "Infectious Diseases and Emerging Antimicrobial Resistance" and goal 14-20 "Hospital Acquired Infections". We have isolated an RNA-binding protein that binds to ica transcript and appears to increase half-life of the RNA and inhibit translation. The immediate goal of this proposed project is to further characterize the post- transcriptional regulatory mechanism bv which this RNA-binding protein regulates ica expression and PNAG production. Short Description. Staphylococcus aureus is an important pathogen that can cause a variety of infections. Antibiotic resistance in S. aureus is common and the problem is compounded by its ability to form adherent, polysaccharide-encased communities called biofilms. The goal of our research is to characterize the mechanism by which biofilm formation is regulated in S. aureus. Understanding the mechanism of biofilm regulation could lead to the development of anti-biofilm therapies that would act synergistically with conventional antibiotics.