Development of Non-Natural Flavanones as Antimicrobial Agents 英文参考文献.docVIP

DevelopmentofNon-NaturalFlavanonesas AntimicrobialAgents ZacharyL.Fowler1,KaranShah2,JohnC.Panepinto3,AmyJacobs3,MattheosA.G.Koffas4* 1Praxair,Inc.BioPharmaResearchandDevelopment,BurrRidge,Illinois,UnitedStatesofAmerica,2DepartmentofChemicalandBiologicalEngineering,Universityat Buffalo,theStateUniversityofNewYork,Buffalo,NewYork,UnitedStatesofAmerica,3DepartmentofMicrobiologyandImmunology,UniversityatBuffalo,theState UniversityofNewYork,Buffalo,NewYork,UnitedStatesofAmerica,4DepartmentofChemicalEngineering,RensalearPolytechnicInstitute,Troy,NewYork,UnitedStates ofAmerica Abstract With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has beenshowntoincreasetheeffectivenessofexistingmoleculesforsomeinfections,oftenwiththeseaddedcompounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondarymetabolitesandhavebeenshowntohavenaturalabilitiesasmicrobialdeterrentsandanti-infectionagentsin plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogensCryptococcusneoformansandAspergillusfumigatus.Ofthosescreened,weidentifiedthesyntheticmolecule4- chloro-flavanoneasthemostpotentantimicrobialcompoundwithaMICvalueof70 mg/mLinE.coliwhencombinedwith theinhibitorPhe-Arg-?-naphthylamide,andMICsof30mg/mLinS.cerevesiaeand30mg/mLinC.neoformanswhenused alone.Throughthisstudywehavedemonstratedthatcombinatorialsyn