Mechanisms of Antimicrobial Peptide Action and Res

MechanismsofAntimicrobialPeptideActionandResistanceMICHAELR.YEAMANANDNANNETTEY.YOUNTDivisionofInfectiousDiseases,Harbor-UniversityofCaliforniaLosAngeles(UCLA)MedicalCenter;St.John’sCardiovascularResearchCenter,Harbor-UCLAResearchandEducationInstitute,Torrance,California;andUCLASchoolofMedicine,LosAngeles,CaliforniaAbstract................................................................................28I.Introduction.............................................................................28II.Mechanismsofantimicrobialpeptidetargetspecificityandselectivetoxicity...................29A.Comparativemembranearchitectureandenergy........................................291.Membranecomposition,hydrophobicity,andcharge...................................292.Membraneasymmetry.............................................................303.Microbialligandsforantimicrobialpeptides..........................................304.Transmembranepotential..........................................................31B.Antimicrobialpeptidestructure-basedselectivetoxicity...................................31C.Invivopreferentialaffinityformicroorganismsversusmammaliancells...................32D.Antimicrobialpeptidelocalizationtorestrictexposureofvulnerablehosttissues............32E.Themesintargetaffinityandselectivetoxicityofantimicrobialpeptides...................33III.Mechanismsofantimicrobialpeptideaction................................................33A.Structuraldeterminantsofantimicrobialpeptideactivity.................................331.Conformation(
)...................................................................342.Charge(Q)........................................................................343.Amphipathicity(A)andhydrophobicmoment(MH)....................................354.Hydrophobicity(H).................................................................355.Polarangle().....................................................................36B.Commonthemesinstructuraldeterminantsofantimicrobialpeptides.....................36C.Initialpeptideinteractionswithmembranetargets......................................371.Electrostaticinteractions...........................................................372.Receptor-mediatedmembraneinteractions...........................................37D.Eventssubsequenttoinitialmembranebinding.........................................381.Thresholdconcentration............................................................382.Conformationalphasetransition....................................................383.Self-associationandmultimerization.................................................394.Thebarrel-stavemechanism........................................................395.Thetoroidporeorwormholemechanism.............................................406.Thecarpetmechanism.............................................................40E.Mechanismsofcelldeath..............................................................411.Membranedysfunction.............................................................412.Inhibitionofextracellularbiopolymersynthesis.......................................423.Inhibitionofintracellularfunctions..................................................42F.Synergyamongantimicrobialpeptides..................................................43G.Themesinmechanismsofactionofantimicrobialpeptides................................43IV.Mechanismsofantimicrobialpeptideresistance.............................................43A.Constitutiveandinducibleresistance...................................................44B.Constitutive(passive)resistance.......................................................441.Inherentmechanismsofresistancetoantimicrobialpeptides...........................44Addresscorrespondenceto:Dr.MichaelR.Yeaman,UCLASchoolofMedicine,DivisionofInfectiousDiseases,St.John’sCardiovascularResearchCenter,Harbor-UCLAResearchandEducationInstitute,1124WestCarsonStreet,RB-2,Torrance,CA90502.E-mail:[e-mail],publicationdate,andcitationinformationcanbefoundat–55$7.00PHARMACOLOGICALREVIEWSVol.55,No.1Copyright©2003byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics30102/1039461PharmacolRev55:27–55,2003PrintedinU.S.A272.Alteredmembraneenergetics.......................................................453.Electrostaticshielding..............................................................454.Niche-specificresistance............................................................46C.Inducible(adaptive)resistance.........................................................461.Coordinatemicrobialresponsestoantimicrobialpeptidestress.........................472.Adaptivemechanismsofresistancetoantimicrobialpeptides...........................483.Proteasesandpeptidases...........................................................484.Extracellularstructuralmodifications.....................................