Novel antibacterial target: an essential glycoprotease

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DESCRIPTION (provided by applicant): The emergence of multi-drug resistant bacterial pathogens, especially methicillin-resistant and vancomycin intermediate-resistant Staphylococcus aureus is generating an enormous public health concern. Many of these pathogens are capable of causing severe and even fatal infections with limited options for therapy. The slowdown in the discovery of novel classes of antibiotics in past several decades and the recent downturn in antibacterial discovery and development in the pharmaceutical industry is making us more vulnerable to emerging resistance. Therefore, there is an urgent need for new, alternative agents for treating multi-drug-resistant pathogens. The recent availability of the complete genome sequences for pathogens enables us to undertake a systematic and comprehensive evaluation of the requirement for each and every gene/operon for both bacterial growth and infection. The gene products essential for bacterial growth in vitro and survival during infection constitute an initial set of validated protein targets that can be optimized and automated screens. Our long-term goal is to identify novel targets for delivering efficacious preventive and/or therapeutic agents against S. aureus infections. The specific hypothesis is that a putative glycoprotease (Gcp) is a novel antibacterial target involved in the pathway required for bacterial survival. However, the biological function of Gcp and its importance for growth and survival remains unclear. Elucidation of the precise function of Gcp will lead to the basis for the development of an in vitro assay, which is indispensable for the drug discovery. Therefore, the objective of this proposal is to determine the biological function of Gcp, identify pathway that Gcp is involved in, and to develop a potential assay. We will pursue the following three specific aims to test our central hypothesis: First, we will characterize the essential putative glycoprotease of S. aureus. Second, we will employ microarray technology to identify staphylococcal genes, transcriptions of which are affected by conditional inactivation of putative glycoprotease function. Third, we will utilize proteomic approaches to identify proteins that are affected by down-regulation of gcp expression and compare this data with microarray data.