抗菌药物选择压力下的布鲁氏菌突变特征的分析-analysis of brucella mutation characteristics under antimicrobial drug selection pressure.docx

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2018-05-29 发布于上海
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抗菌药物选择压力下的布鲁氏菌突变特征的分析-analysis of brucella mutation characteristics under antimicrobial drug selection pressure.docx

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抗菌药物选择压力下的布鲁氏菌突变特征的分析-analysis of brucella mutation characteristics under antimicrobial drug selection pressure

AbstractBrucellosisisontheriseinmanyregionsinChina.AntibiotictherapyisthefirstchoicetotreattheBrucella-infectedpatients.Sinceimproperuseofantibioticsleadstoresistancemutation,correctlychoosingtheantibioticsforthetreatmentofBrucellainfectionisveryimportant.Toassistdoctorstodosetheantibiotics,atheoryofmutantpreventionhasbeenproposedstatingthatadosageofanantibioticabovetheminimalinhibitoryconcentration(MIC)butbelowthemutantpreventionconcentration(MPC)killssensitivebacteriabutenrichestheresistancemutants;therefore,dosagebetweenMICandMPCiscalledmutantselectionwindow(MSW).Inordertoavoidresistance,antibioticswithlowerMPCshouldbeusedsodosageaboveMPCcanbeeasilyachieved.Inthepresentproject,MSWandselectionindex(SI=MPC/MIC)forfourantibiotics(rifampin,rifabutin,cefdinir,cephalosporincefepime)toBrucellastrainsS2weredeterminedbybrothdilutionmethodandagardilutionmethod;MSWswere4-460μg/mL,0.703-512μg/mL,0.2361-0.5764,and0.0083μg/mL-0.2951μg/mLandSIswere115,728,2.44,andforthe4antibioticsrespectively.OurresultsindicatedthatcefdinirandcephalosporincefepimehavefavorableMSWandSIforpreventingtheantibioticresistance;rifampinandrifabutinwerepronetogeneratedrugresistance.Tofurtherunderstandingtheresistance,mutationsinthedrugtargetcodinggeneswerecharacterizedbysequencingtheDNAextractedfromtheselectedcoloniesunderdifferentdrugconcentrations.RifampinandrifabutinresistantmutationswerefoundatH536Y,S532L,H536R,R539HaminoacidresiduesintherpoBgene.Inaddition,rifampicinselectedQ523Lwhilerifabutinselectedthe521~523LSQ(1561~1569bp)deletion,Q523KandS541Lmutation.ThepenAgenethatencodesthetargetforcephalosporinwasfoundmutatedwithintheaminoacidsequence385to560withN477S,S484L,andA559DpointmutationweremostcommonfollowedbyF519I,L387F,A559T,G485V,T499Smutations;withincreaseofthedrugconcentration,eventuallyonlyG485VT499Sremained.InthemrcAgenethatencodesthetargetforcefdinirnomutationswerefound,inconsistencewithitslowMPCandsmallSI.Ourstudiesshouldprovideusefulinformationfordoctorsinchoosingtherightantibioticstotr