End-Tagging of Ultra-Short Antimicrobial Peptides by WF Stretches to Facilitate Bacterial Killing 英文参考文献.docVIP

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End-Tagging of Ultra-Short Antimicrobial Peptides by WF Stretches to Facilitate Bacterial Killing 英文参考文献.doc

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End-Tagging of Ultra-Short Antimicrobial Peptides by WF Stretches to Facilitate Bacterial Killing 英文参考文献

End-TaggingofUltra-ShortAntimicrobialPeptidesby W/FStretchestoFacilitateBacterialKilling MukeshPasupuleti1,ArturSchmidtchen1,AnnaChalupka1,LovisaRingstad2,MartinMalmsten2* 1SectionofDermatologyandVenereology,DepartmentofClinicalSciences,LundUniversity,Lund,Sweden,2DepartmentofPharmacy,UppsalaUniversity,Uppsala, Sweden Abstract Background: Due to increasing resistance development among bacteria, antimicrobial peptides (AMPs), are receiving increasedattention.Ideally,AMPshoulddisplayhighbactericidalpotency,butlowtoxicityagainst(human)eukaryoticcells. Additionally,shortandproteolyticallystableAMPsaredesiredtomaximizebioavailabilityandtherapeuticversatility. Methodology and Principal Findings: A facile approach is demonstrated for reaching high potency of ultra-short antimicrobal peptides through end-tagging with W and F stretches. Focusing on a peptide derived from kininogen, KNKGKKNGKH(KNK10)andtruncationsthereof,end-taggingresultedinenhancedbactericidaleffectagainstGram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Through end-tagging, potency and salt resistance could be maintained down to 4–7 amino acids in the hydrophilic template peptide. Although tagging resulted in increased eukaryoticcellpermeabilizationatlowionicstrength,thelatterwasinsignificantatphysiologicalionicstrengthandinthe presenceofserum.Quantitatively,themostpotentpeptidesinvestigateddisplayedbactericidaleffectscomparableto,orin excess of, that of the benchmark antimicrobial peptide LL-37. The higher bactericidal potency of the tagged peptides correlatedtoahigherdegreeofbindingtobacteria,andresultingbacterialwallrupture.Analogously,taggingenhanced peptide-inducedruptureofliposomes,particularlyanionicones.Additionally,end-taggingfacilitatedbindingtobacterial lipopolysaccharide,botheffectsprobablycontributingtotheselectivitydisplayedbythesepeptidesbetweenbacteriaand eukaryoticcells.Importantly,W-taggingresultedinpeptideswithmaintainedstabilityagainstproteolyticdegradationby human