A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen 英文参考文献.docVIP

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A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen 英文参考文献.doc

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A Novel In Vitro Multiple-Stress Dormancy Model for Mycobacterium tuberculosis Generates a Lipid-Loaded, Drug-Tolerant, Dormant Pathogen 英文参考文献

ANovelInVitroMultiple-StressDormancyModelfor MycobacteriumtuberculosisGeneratesaLipid-Loaded, Drug-Tolerant,DormantPathogen ChirajyotiDeb,Chang-MukLee,VinodS.Dubey,JaiyanthDaniel,BassamAbomoelak,TatianaD. Sirakova,SantoshPawar,LindaRogers,PappachanE.Kolattukudy* BurnettSchoolofBiomedicalSciences,CollegeofMedicine,UniversityofCentralFlorida,Orlando,Florida,UnitedStatesofAmerica Abstract Background: Mycobacterium tuberculosis (Mtb) becomes dormant and phenotypically drug resistant when it encounters multiplestresseswithinthehost.InabilityofcurrentlyavailabledrugstokilllatentMtbisamajorimpedimenttocuringand possibly eradicating tuberculosis (TB). Most in vitro dormancy models, using single stress factors, fail to generate a truly dormantMtbpopulation.AninvitromodelthatgeneratestrulydormantMtbcellsisneededtoelucidatethemetabolic requirementsthatallowMtbtosuccessfullygothroughdormancy,identifynewdrugtargets,andtoscreendrugcandidates todiscovernoveldrugsthatcankilldormantpathogen. Methodology/Principal Findings: We developed a novel in vitro multiple-stress dormancy model for Mtb by applying combinedstressesoflowoxygen(5%),highCO2(10%),lownutrient(10%Dubosmedium)andacidicpH(5.0),conditions Mtb is thought to encounter in the host. Under this condition, Mtb stopped replicating, lost acid-fastness, accumulated triacylglycerol(TG)andwaxester(WE),andconcomitantlyacquiredphenotypicantibiotic-resistance.Putativeneutrallipid biosynthetic genes were up-regulated. These genes may serve as potential targets for new antilatency drugs. The triacylglycerol synthase1 (tgs1) deletion mutant, with impaired ability to accumulate TG, exhibited a lesser degree of antibiotic tolerance and complementation restored antibiotic tolerance. Transcriptome analysis with microarray revealed theachievementofdormantstateshowingrepressionofenergygeneration,transcriptionandtranslationmachineriesand inductionofstress-responsivegenes.WeadaptedthismodelfordrugscreeningusingtheAlamarBluedyetoquantifythe ant