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. Antibiotic resistance in Streptococcus pneumoniae has increased dramatically over the last twenty years. Although resistance with the different classes of antimicrobials occurs through dissimilar mechanisms, the presence of gene mutations most commonly with penicillin resistance appears to be a marker for the acquisition of gene mutations consistent with resistance to other antimicrobial classes. Currently, limited information is available about the alterations in gene expression that occur after S. pneumoniae acquires mutations resulting in antimicrobial resistance. Furthermore, nothing is known about how the host alters gene expression in antibiotic resistant S. pneumoniae. Our long term goal is to determine the influence of host factors on gene expression in antibiotic resistant S. pneumoniae to identify potential therapeutic drug targets. The objective of this application is to determine what genes are altered (up-regulated or down-regulated) in antibiotic resistant S. pneumoniae following exposure to host or human cells. The central hypothesis is that specific genes that control regulation, transport and signaling are involved in antibiotic resistance and host or human cells alter the gene expression. This hypothesis has been formulated on reports in the literature linking genetic regulatory systems to antimicrobial resistance and antimicrobial tolerance. The rationale for the proposed research is that once these genes are identified, they can be altered pharmacologically in new and innovative approaches for the treatment of individuals infected with antibiotic resistant pneumococci. The central hypothesis will be tested and the objective of this application will be met by pursuing two specific aims: 1) Classify the genes with altered expression in antibiotic-resistant S. pneumoniae isolates 2) Categorize the genes with altered expression in isolates selected for antibiotic resistance in the presence of human cells and sub-therapeutic antibiotic concentrations, and 3) Identify gene expression changes in S. pneumoniae when it is exposed to host cells, sub-therapeutic antibiotic concentration and other bacterial species that are often clinically involved in transformation of antibiotic resistant determinant. This planned proposal is innovative because it employs a new technology that allows whole genome analysis simultaneously. It is our expectation that the proposed approach will identify the genetic alterations that occur in antibiotic resistant isolates that are exposed to host cells. These outcomes will be significant because we will obtain an understanding of the complex interaction between regulators of gene expression following the occurrence of resistance with several antimicrobial classes. This work will lead to the identification of new therapeutic drug targets for the treatment of infections caused by resistant Streptococcus pneumoniae.
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