This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many pathogenic bacteria that affect millions of people worldwide, including some that are classified as potential agents of bioterrorism, use a type III secretion needle apparatus on their cell surface to inject toxic proteins into human host cells. No vaccines are currently approved for general use against any of these pathogens, and the appearance of antibiotic resistant strains makes these pathogens major threats to public health and safety. Because the needle apparatus is critical for virulence and is exposed on the bacterial surface, disrupting this protein assembly is an attractive approach for the development of novel antibiotics. This approach requires a detailed understanding of the protein-protein interactions involved in the assembly of the needle apparatus. The needle is assembled from about 120 identical copies of a protein that are arranged in a helical manner, and the tip of needle is capped by a few copies of a special tip protein. Our long term goal is to determine precisely how the needle apparatus is assembled from its protein components. We propose here to elucidate the protein-protein interactions of BsaL and BipD, the needle and tip proteins of Burkholderia pseudomallei, which is a pathogen associated with bioterrorism and endemic infectious disease in Thailand and Northern Australia, using a combination of NMR, mutagenesis, and bacterial invasion assays in cell culture. In the longer term the knowledge gained will be applied to devising small molecule strategies to disrupt needle assembly and thereby render virulent bacteria non-virulent.
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