PEGylating a bacteriophage endolysin inhibits its bactericidal activity 英文参考文献.docVIP

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PEGylating a bacteriophage endolysin inhibits its bactericidal activity 英文参考文献.doc

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PEGylating a bacteriophage endolysin inhibits its bactericidal activity 英文参考文献

Reschetal.AMBExpress2011,1:29 /content/1/1/29 ORIGINAL OpenAccess PEGylatingabacteriophageendolysininhibitsits bactericidalactivity GregoryResch1,2*,PhilippeMoreillon2andVincentAFischetti1 Abstract Bacteriophageendolysins(lysins)bindtoacellwallsubstrateandcleavepeptidoglycan,resultinginhypotoniclysis ofthephage-infectedbacteria.WhenpurifiedlysinsareaddedexternallytoGram-positivebacteriatheymediate rapiddeathbythesamemechanism.Forthisreason,noveltherapeuticstrategieshavebeendevelopedusingsuch enzybiotics.However,likeotherproteinsintroducedintomammalianorganisms,theyarequicklyclearedfrom systemiccirculation.PEGylationhasbeenusedsuccessfullytoincreasetheinvivohalf-lifeofmanybiological moleculesandwasthereforeappliedtoCpl-1,alysinspecificforS.pneumoniae.Cysteine-specificPEGylationwith eitherPEG10Kor40KwasachievedonCpl-1mutants,eachcontaininganadditionalcysteineresidueatdifferent locationsTothebestofourknowledge,thisisthefirstreportofthePEGylationofbacteriophagelysin.Compared tothenativeenzyme,noneofthePEGylatedconjugatesretainedsignificantinvitroanti-pneumococcallytic activitythatwouldhavejustifiedfurtherinvivostudies.Sincetheanti-microbialactivityofthemutantenzymes usedinthisstudywasnotaffectedbytheintroductionofthecysteineresidue,ourresultsimpliedthatthe presenceofthePEGmoleculewasresponsiblefortheinhibition.Asmostendolysinsexhibitasimilarmodular structure,webelievethatourworkemphasizestheinabilitytoimprovetheinvivohalf-lifeofthisclassof enzybioticsusingacysteine-specificPEGylationstrategy. Keywords:Bacteriophage,S.pneumoniae,Cpl-1,PEGylation,Endolysin,Enzybiotic Introduction repeated injections or continuous infusion (Entenza et Streptococcus pneumoniae is the first cause of otitis al.,2005,).Werecentlyshowedthatpre-dimerizationof media and a common cause of sinusitis, community- Cpl-1, which doubles the molecular weight of the acquiredpneumonia,bacteremia,andmeningitis(Jacobs, enzyme, decreased its plasma clearance by a factor of 2004,). Antibiotic misuseand