Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression 英文参考文献.docVIP

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Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression 英文参考文献.doc

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Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression 英文参考文献

EvaluatingtheSensitivityofMycobacteriumtuberculosis toBiotinDeprivationUsingRegulatedGeneExpression SaeWoongPark1,MarcusKlotzsche1,DanielJ.Wilson2,HelenaI.Boshoff3,HyungjinEoh4 ,Ujjini Manjunatha5,AntjeBlumenthal1,KyuRhee4,CliftonE.Barry,III3,CourtneyC.Aldrich2,SabineEhrt1*, DirkSchnappinger1* 1DepartmentofMicrobiologyandImmunology,WeillCornellMedicalCollege,NewYork,NewYork,UnitedStatesofAmerica,2CenterforDrugDesign,Universityof Minnesota,Minneapolis,Minnesota,UnitedStatesofAmerica,3TuberculosisResearchSection,NationalInstituteofAllergyandInfectiousDiseases,Bethesda,Maryland, United States of America, 4Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America, 5Novartis Institute for Tropical Diseases,Singapore Abstract In the search for new drug targets, we evaluated the biotin synthetic pathway of Mycobacterium tuberculosis (Mtb) and constructedanMtbmutantlackingthebiotinbiosyntheticenzyme7,8-diaminopelargonicacidsynthase,BioA.Inbiotin-free synthetic media, DbioA did not produce wild-type levels of biotinylated proteins, and therefore did not grow and lost viability.DbioAwasalsounabletoestablishinfectioninmice.Conditionally-regulatedknockdownstrainsofMtbsimilarly exhibitedimpairedbacterialgrowthandviabilityinvitroandinmice,irrespectiveofthetimingoftranscriptionalsilencing. BiochemicalstudiesfurthershowedthatBioAactivityhastobereducedbyapproximately99%topreventgrowth.These studiesthusestablishthatdenovobiotinsynthesisisessentialforMtbtoestablishandmaintainachronicinfectionina murinemodelofTB.Moreover,thesestudiesprovideanexperimentalstrategytosystematicallyranktheinvivovalueof potentialdrugtargetsinMtbandotherpathogens. Citation:WoongParkS,KlotzscheM,WilsonDJ,BoshoffHI,EohH,etal.(2011)EvaluatingtheSensitivityofMycobacteriumtuberculosistoBiotinDeprivation UsingRegulatedGeneExpression.PLoSPathog7(9):e1002264.doi:10.1371/journal.ppat.1002264 Editor:MarcelA.Behr,McGillUniversity,Canada ReceivedApril10,2011;AcceptedJuly28,201