ThelongtermgoalsoftheprojectaretoidentifythefullarrayofeffluxpumpsofStaphylococcusaureus thatcontributetomultipleantimicrobialresistanceandtoelucidatethedeterminantsoftheirexpression, theirroleinmicrobialphysiologyandtheireffectonbacterialresponsetoantimicrobialsininfection.The work will focus on genetic analysis of regulatory elements and on bacterial fitness and response to antimicrobials in a subcutaneous abscess model, collaborating with other project groups to assess the efficacyofnovelantimicrobialcompoundsinabscessesandtheextenttowhicheffluxpumpsaffectthat efficacy.Therearefourspecificaims:1)analyzetheglobalarrayofeffluxpumpsofS.aureusfortheir effects on susceptibility to established antimicrobials and novel compounds identified by P01 collaborators;2)analyzetheeffectsofphysiologicpumpoverexpressionintheabscessenvironmentand on treatment response to antimicrobials with focus on the Tet38 pump and tetracycline treatment; 3) dissect the regulatory networks affecting resistance effux pump expression using the high?efficiency multiplexlibrariesdevelopedbytheWalkerlab;and4)testnovelcompoundsfromP01collaboratorsfor efficacy in mammalian infection and biofilm models and assess the moonlighting model in the abscess model.TheworkwillutilizegeneticmanipulationandallelicexchangeinS.aureus,measurementsofgene expression with RT?PCR, and established murine models of infection (subcutaneous abscess, renal abscess,lethality)utilizingagenomicallydefinedstrainsofmethicillin?resistantandotherS.aureus.The overall goal of the program project is to take a well?integrated, multi?disciplinary approach to understandingantibioticresistancedevelopmentandtransmission,andtointegratethateffortwiththe search for compounds that compromise resistant pathogens, including methicillin?resistant S. aureus (MRSA), by inhibiting novel targets and pathways. This project will add to understanding of resistance mechanismsrelatedtomultidrugeffluxpumpsandprovidestrainsfortestingtheeffectofsuchpumps onnovelcompoundsactiveagainstnewtargetsandpathways.Itwillalsoutilizemammalianmodelsofa commonMRSAinfectiontotestcompoundactivityinvivo.
Multidrug resistance in S. aureus is an increasing clinical and public health problem that requires additional understanding of its mechanisms of development and spread and establishment of novel targetsthatmaybeexploitedtodevelopneweffectivetherapies.
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