Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant 英文参考文献.docVIP

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Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant 英文参考文献.doc

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Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant 英文参考文献

MolecularBasisofNDM-1,aNewAntibioticResistance Determinant ZhongjieLiang1.,LianchunLi1,2.,YuanyuanWang1.,LiminChen1,XiangqianKong1,YaoHong2 ,Lefu Lan1,MingyueZheng1,CaiGuang-Yang1,HongLiu1,XuShen1,ChengLuo1,3*,KeqinKathyLi2* ,Kaixian Chen1,HualiangJiang1,4* 1DrugDiscoveryandDesignCenter,StateKeyLaboratoryofDrugResearch,ShanghaiInstituteofMateriaMedica,ChineseAcademyofSciences,Shanghai,China,2State KeyLaboratoryofMedicalGenomics,ShanghaiInstituteofHematology,RuiJinHospitalAffiliatedtoShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai,China, 3CenterforSystemsBiology,SoochowUniversity,Jiangsu,China,4SchoolofPharmacy,EastChinaUniversityofScienceandTechnology,Shanghai,China Abstract TheNewDelhiMetallo-b-lactamase(NDM-1)wasfirstreportedin2009inaSwedishpatient.Arecentstudyreportedthat KlebsiellapneumoniaNDM-1positivestrainorEscherichiacoliNDM-1positivestrainwashighlyresistanttoallantibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomespotentiallyamajorglobalhealththreat. Inthisstudy,weperformedmodelingstudiestoobtainits3Dstructure andNDM-1/antibioticscomplex.Itrevealedthatthehydrolyticmechanismsarehighlyconserved.Inaddition,thedetailed analysis indicates that the more flexible and hydrophobic loop1, together with the evolution of more positive-charged loop2 leads to NDM-1 positive strain more potent and extensive in antibiotics resistance compared with other MBLs. Furthermore, through biological experiments, we revealed the molecular basis for antibiotics catalysis of NDM-1 on the enzymatic level. We found that NDM-1 enzyme was highly potent to degrade carbapenem antibiotics, while mostly susceptibletotigecycline,whichhadtheabilitytoslowdownthehydrolysisvelocityofmeropenembyNDM-1.Meanwhile, the mutagenesis experiments, including D124A, C208A, K211A and K211E, which displayed down-regulation on meropenem catalysis, proved the accuracy of our model. At present, there are no effective ant