Post-transcriptional regulation of biofilm formation S. aureus

描述（由申请人提供）：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。金黄色葡萄球菌的抗生素耐药性是一个严重的临床问题，这种生物在人体组织和插入的医疗设备（如导尿管）上形成生物膜的能力使其更加复杂。在适当的环境条件下，大多数金黄色葡萄球菌菌株能够形成一种表面相关（3-1-1 -6）的n -乙酰氨基葡萄糖（PNAG）聚合物，具有两种重要的毒力功能：1。它是生物膜外聚合物基质的主要组成部分。它在感染期间保护细菌不被吞噬。在感染过程中，生物膜的形成通常会导致细菌群对抗菌化疗难以耐受，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，细胞间黏附素（ica）位点编码参与PNAG合成的四种蛋白，ica、IcaD、IcaB和IcaC，似乎在毒力中起关键作用，这并不奇怪。目前金黄色葡萄球菌感染的治疗方式可以通过抑制耐药生物膜的形成来显着改善。该项目的长期目标是表征金黄色葡萄球菌对PNAG细化和随后生物膜形成的调控。深入了解这一途径将有助于确定抗生物膜治疗剂的靶点，从而与传统抗生素协同作用。这有助于实现2010年健康人防治“传染病和新出现的抗菌素耐药性”的目标和目标14-20 “医院获得性感染”的目标。我们已经分离出一种RNA结合蛋白，它与ica转录物结合，似乎增加了RNA的半衰期并抑制了翻译。该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。简短描述。金黄色葡萄球菌是一种重要的病原体，可引起多种感染。金黄色葡萄球菌对抗生素的耐药性是常见的，而且这个问题由于金黄色葡萄球菌能够形成附着的、被多糖包裹的被称为生物膜的群落而变得更加复杂。我们的研究目的是表征的机制，其中生物膜的形成是在金黄色葡萄球菌调节。了解生物膜调控的机制可能会导致抗生物膜疗法的发展，这将与传统抗生素协同作用。

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.