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Development of Anti-Biofilm Agents that Target Staphylococcal Biofilms

开发针对葡萄球菌生物膜的抗生物膜剂

基本信息

批准号：
8376872
负责人：
Roberto G. Kolter
金额：
$ 37.55万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8376872
关键词：
Acids Affect Amino Acids Antibiotic Resistance Antibiotics Bacillus subtilis Bacteria Binding Biological Models Cell Surface Proteins Cell-Matrix Junction Cells Complex Development Devices Eukaryotic Cell Experimental Designs Extracellular Matrix Funding Gene Expression Genes Glucosamine Grant Growth Individual Infection Instruction Knowledge Laboratories Lead Life Cycle Stages Lipids Mediating Membrane Membrane Microdomains Methicillin Microbial Biofilms Modality Molecular Nosocomial Infections Organism Pathway interactions Peptidoglycan Physiology Process Proteins Research Resistance Resistance development Role Route Signal Transduction Skin Staphylococcus aureus Surface Teichoic Acids Vancomycin Vancomycin-resistant S. aureus Virulence base combat experience implantable device implantation inhibitor/antagonist methicillin resistant Staphylococcus aureus minimal risk pathogen prevent programs tool

项目摘要

PROJECT SUMMARY (See instructions): Staphylococcus aureus is key pathogen involved in nosocomial infections, frequently due to biofilm formation on indwelling devices. Once biofilms grow on these surfaces they are difficult to eradicate because the constituent cells display increased resistance to many antibiotics. This, combined with the fact that a large percentage of S. aureus isolates identified in infections now harbor resistance genes against numerous antibiotics including methicillin and vancomycin (MRSA, VRSA), makes it clear that new ways of combating staphyloccocal biofilm-associated infections need to be developed. This subproject ofthe Harvard-wide collaborative project for new MRSA treatments is focused on the development of anti-biofilm agents that target staphyloccocal biofilms. We have recently discovered two distinct mechanisms for inhibiting biofilm formation in a broad range of organisms, including S. aureus. The first mechanism is based on the finding that bacteria organize many membrane-related processes in functional microdomains that involve unusual lipids, i.e. bacteria have lipid rafts akin to those is found in eukaryotic cells. Interfering with the synthesis of these usual lipids can lead to complete elimination of biofilm formation without a lethal effect on the cells. The second discovery is that bacteria produce D-amino acids late in the life cycle of a biofilm and that these amino acids are incorporated into the peptidoglycan with the consequence that cells are released from the biofilm matrix and the biofilm is thus disassembled. While these processes have been analyzed in detail in the bacterium Bacillus subtilis, little is known about the mechanisms by which lipid synthesis inhibitors or Damino acids prevent biofilm formation in S. aureus. To this end, we propose to: 1) Identify the lipid raft fomiation pathway in S. aureus and determine the mechanism through which anti-lipid raft agents inhibit biofilm formation, and 2) Determine the molecular mechanism through which D-amino acids affect S. aureus biofilms.

项目概述（见说明）：