Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans.docVIP

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Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans.doc

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Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans

AntifungalActivityofFusedMannichKetonesTriggers anOxidativeStressResponseandIsCap1-Dependentin Candidaalbicans TristanRossignol1,2¤a,Be′laKocsis3,OrsolyaBouquet4,Ildiko′ Kustos5,FerencKila′r4,AdrienNyul3, Pe′terB.Jakus6,KshitijRajbhandari7¤b,La′szlo′ Pro′kai7,Christophed’Enfert1,2,Tama′sLo′ra′nd6* 1InstitutPasteur,Unite′BiologieetPathoge′nicite′Fongiques,De′partementGe′nomesetGe′ne′tique,Paris,France,2INRA,USC2019,Paris,France,3DepartmentofMedical MicrobiologyandImmunology,FacultyofMedicine,UniversityofPe′cs,Pe′cs, Hungary,4InstituteofBioanalysis,FacultyofMedicine,UniversityofPe′cs,Pe′cs,Hungary, 5DepartmentofMicrobiology,AlderHeyChildren`sNHSFoundationTrust,Liverpool,UnitedKingdom,6DepartmentofBiochemistryandMedicalChemistry,Facultyof Medicine,UniversityofPe′cs,Pe′cs, Hungary,7DepartmentofMolecularBiologyandImmunology,UniversityofNorthTexasHealthScienceCenter,FortWorth,Texas, UnitedStatesofAmerica Abstract WeinvestigatedtheantifungalactivityoffusedMannichketone(FMK)congenersandtwooftheiraminoalcoholderivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC s) 90 rangingfrom0.8to6mg/mLtowardC.albicansandthecloselyrelatedC.parapsilosisandC.kruseiwhilehavingreduced efficacytowardC.glabrataandalmostnoefficacyagainstAspergillussp.TranscriptprofilingofC.albicanscellsexposedfor 30or60minto2-(morpholinomethyl)-1-indanone,arepresentativeFMKwithafive-memberedsaturatedring,revealeda transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently,C.albicanslackingtheCAP1genewashypersensitivetothisFMK,whileC.albicansstrainsoverexpressingCAP1 haddecreasedsensitivityto2-(morpholinomethyl)-1-indanone.Quantitativestructure–activityrelationshipstudiesrevealed acorrelationofantifungalpotencyandtheenergyofthelowestunoccupiedmolecularorbitalofFMKsandunsaturated Mannichketonestherebyimplicatingredoxcycling-mediatedoxidativestressasamech