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In nature, bacteria grow predominantly within sessile, matrix-enclosed communities known as biofilms, rather than as unattached planktonic cells. Biofilms protect resident bacteria and complicate many chronic infections by preventing immune function, compromising antimicrobial therapy, and dispersing planktonic cells that spread infection to distant body sites. <p> Our long-term goal is to obtain fundamental understanding of the interrelated structural, enzymatic, and regulatory elements required for biofilm formation and dispersal as a prerequisite for developing approaches to combat biofilm-related infections. While diverse structural components and regulatory stragtegies affect biofilm formation, we hypothesize that there are a few critical factors that are of importance in many species, which are best studied in model organisms. One such factor is the RNA-binding protein CsrA, a global regulator that controls biofilm formation in many species. In Escherichia coli, CsrA represses biofilm formation, while it activates biofilm dispersal and motility. The most important role of CsrA in biofilm formation is to inhibit translation and stimulate decay of pgaABCD mRNA, which is needed for the production and transport of poly-beta-1,6-N-acetyl-D-glucosamine (PGA). This polysaccharide adhesin stabilizes biofilms of diverse species and promotes disease transmission and/or virulence in certain pathogens.<p> We will define other processes by which CsrA regulates biofilm formaion. Regulators of pgaABCD gene expression have profound effects on biofilm development, incuding NhaR, a transcriptional activator, and CsrD, a novel Csr-system component. Our preliminary studies reveal two additional important regulatory systems that control biofilm formation and PGA production without affecting pgaABCD gene expression. We will define these two novel regulatory circuits.
Non-Technical Summary: Bacterial growth attached to surfaces in slimy coatings is referred to as a biofilm. In this state, bacterial cells are very resistant to stresses, including antibiotic treatment and disinfection. Many of the important diseases of humans, animals and plants are complicated by the fact that bacterial are associated with host tissues or foreign objects such as catheters, implants and prosthetic devices as biofilms. By identifying and studying the bacterial genes, proteins, adhesins and other factors that participate in biofilm formation, it may be possible to develop drugs or procedures to prevent or treat biofilm-related infections. We have already identified an important polysaccharide that serves as a crucial adhesin for many kinds of bacterial biofilms, and have found several ways in which the bacterial cell controls the synthesis of this polysaccharide. We propose to define additional regulatory circuits and factors that control the production of this adesive polysaccharide and other biofilm-related bacterial products. <P> Approach: We will use bacterial genetics, gene fusions, molecular biology, biochemical and immunological approaches to define the novel regulatory circuits that control bacterial biofilm development. The findings will influence workers in a variety of basic fields, including researchers of bacterial genetic circuits, physiology, host-microbe interactions as well as researchers in applied fields, including agriculture, biotechnology, medicine, which are affected positively or negatively by bacterial biofilms,.