Pathogens

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Project Description:

The bacterium Staphylococcus aureus is a serious human pathogen and a public health concern in both community and clinical settings.  Bacterial resistance to antimicrobial agents reduces their chemotherapeutic effectiveness against infectious diseases caused by S. aureus, and in particular, multi-drug resistant strains. The long term objectives of the experiments proposed in this project application are to enhance our understanding of the functional roles of the multidrug efflux pump operon (farABC) and its transcriptional regulatory system (yycFG) in clinical isolates of methicillin resistant S. aureus (MRSA) and vancomycin intermediate S. aureus (VISA), both of which are serious human pathogens. The central hypotheses are that the farABC-encoded efflux pumps mediate intrinsic resistance to fusidic acid and ethidium, provide scaffolding for clinical resistance to arise, and that yycFG elements control transcription of these pump genes, thus contributing to antimicrobial drug resistance. The rationale for these hypotheses is that once the relationships are known between the multidrug efflux pumps and their transcriptional control systems, then insight will be gained regarding Staphylococcal resistance mechanisms to multiple antimicrobial agents, thus allowing for the alteration of conditions that foster resistances and allowing for the enhanced efficacy of chemotherapy of serious infectious diseases. The specific aims are 1: to determine the transcriptional responsiveness of farABC and yycFG loci to multiple mechanistically unrelated antimicrobials. 2: to determine the antimicrobial susceptibility and drug accumulation phenotypes, plus transcriptomes of individually inactivated farA, farB and farC mutants. 3: to determine the effects of yycFG and farC on farABC transcription. The expected outcomes of the proposed experiments are that the training efforts will be facilitated for undergraduate and graduate students plus postdoctoral fellows. The experiments will allow biomedical investigators to collaborate productively within the NM network. The combination of physiological studies (efflux) with transcriptional regulation will provide molecular insight into two important systems for bacterial resistance to antimicrobial agents in a serious human pathogen that is a public health concern in both community and clinical settings.