SkiptomaincontentThankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtainthebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodeinInternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstylesandJavaScript.AdvertisementnaturenaturecommunicationsarticlesarticleModeofactionofteixobactinsincellularmembranesDownloadPDFSubjectsAntibioticsBacterialinfectionDrugdiscoveryanddevelopmentSolid-stateNMRAbstractThenaturalantibioticteixobactinkillspathogenicbacteriawithoutdetectableresistance.Thedifficultsynthesisandunfavourablesolubilityofteixobactinrequiremodifications,yetinsufficientknowledgeonitsbindingmodeimpedesthehuntforsuperioranalogues.Thusfar,teixobactinsareassumedtokillbacteriabybindingtocognatecellwallprecursors(LipidIIandIII).Herewepresentthebindingmodeofteixobactinsincellularmembranesusingsolid-stateNMR,microscopy,andaffinityassays.Wesolvethestructureofthecomplexformedbyanimprovedteixobactin-analogueandLipidIIandrevealhowteixobactinsrecognizeabroadspectrumoftargets.Unexpectedly,wefindthatteixobactinsonlyweaklybindtoLipidIIincellularmembranes,implyingthedirectinteractionwithcellwallprecursorsisnotthesolekillingmechanism.Ourdatasuggestanadditionalmechanismaffordstheexcellentactivityofteixobactins,whichcanblockthecellwallbiosynthesisbycapturingprecursorsinmassiveclustersonmembranes.DownloadPDFIntroductionTeixobactin,thefirstofanewclassofantibiotics,killsabroadspectrumofclinicallyrelevantmulti-drugresistantpathogens,suchasmethicillin-resistantStaphylococcusaureusandMycobacteriumtuberculosiswithexcellentactivity1.TeixobactinisanaturalundecapeptidefromEleftheriaterraethatcomprisesseveraluncommonresiduesincludingd-amino-acidsandl-allo-enduracididine,withthelastfourresiduesformingaringmotif.Giventhatitinhibitsbacterialcellwallsynthesisbytargetingconservednon-proteinogenicmolecules(LipidIIandIII)intheplasma-membrane(Fig. 1a)1,developmentofresistanceagainstteixobactinisdifficult2,3,4.Fig