Antibiotics抗生素

ReviewAntibiotics:Pharmacokinetics,toxicity,resistanceandmultidrugeffluxpumpsÇig˘demYılmaza,b,GülayÖzcengiza,⇑aDepartmentofBiologicalSciences,MiddleEastTechnicalUniversity,06800Ankara,TurkeybDepartmentofBiology,AmasyaUniversity,05100Amasya,TurkeyarticleinfoArticlehistory:Received29August2016Accepted14October2016AvailableonlinexxxxKeywords:AntibioticsPharmacokinetic/pharmacodynamicsToxicityAntibioticresistanceResistomeMultidrugeffluxpumpsabstractThediscoveryofpenicillinfollowedbystreptomycin,tetracycline,cephalosporinsandothernatural,semi-syntheticandsyntheticantimicrobialscompletelyrevolutionizedmedicinebyreducinghumanmorbidityandmortalityfrommostofthecommoninfections.However,shortlyaftertheywereintro-ducedtoclinicalpractice,thedevelopmentofresistancewasemerged.Thedecreasinginterestfromantibioticindustryinspiteofrapidglobalemergenceofantibioticresistanceisatoughdilemmafromthepointviewofpublichealth.Theefficiencyofantimicrobialtreatmentisdeterminedbybothpharma-cokineticsandpharmacodynamics.Inspiteoftheirselectivetoxicity,antibioticsstillcausesevere,life-threateningadversereactionsinhostbodymostlyduetodefectivedrugmetabolismorexcessivedosingregimen.Thepresentarticleaimsatupdatingcurrentknowledgeonpharmacokinetics/pharmacodynamicsconceptsandmodels,toxicityofantibioticsaswellasantibioticresistancemechanisms,resistomeanalysesandsearchfornovelantibioticresistancedeterminantswithspecialemphasisgiventothe-state-of-the-artregardingmultidrugeffluxpumpsandtheiradditionalphysiologicalfunctionsinstressadaptationandvirulenceofbacteria.Alltheseissuesarehighlylinkedtoeachotherandnotonlyimpor-tantformostefficientandprolongeduseofcurrentantibiotics,butalsofordiscoveryanddevelopmentofnewantibioticsandnovelinhibitorsofantibioticresistancedeterminantsofpathogens.
2016ElsevierInc.Allrightsreserved.Contents1.Introduction..........................................................................................................002.Pharmacokinetics/pharmacodynamicsandtoxicityofantibiotics................................................................002.1.Pharmacokinetics/pharmacodynamicsconceptsandmodels..............................................................002.2.Cellularpharmacokineticsandpharmacodynamicsofantibiotics..........................................................002.3.SelectedPK/PDstudiesfordifferentantibioticclasseswithreferencetoparticularpathogens...................................002.4.Toxicityofantibiotics.............................................................................................003.Antibioticresistanceandmultidrugeffluxpumps............................................................................003.1.Generaloutlooktoantibiotic-resistantpathogens,mechanismsofresistanceandtransfer......................................003.2.Resistomesandresistomeanalysisforfindingnovelantibioticresistancedeterminants.......................................003.3.Multidrugeffluxpumps(MDEPs)....................................................................................004.Conclusion...........................................................................................................00Disclosures.............................................................................................................00Acknowledgement.....................................................................................................00References...........................................................................................................00
2016ElsevierInc.Allrightsreserved.⇑Correspondingauthor.E-mailaddress:[e-mail](G.Özcengiz).BiochemicalPharmacologyxxx(2016)xxx–xxxContentslistsavailableatScienceDirectBiochemicalPharmacologyjournalhomepage::Ç.Yılmaz,G.Özcengiz,Antibiotics:Pharmacokinetics,toxicity,resistanceandmultidrugeffluxpumps,Biochem.Phar-macol.(2016),ficationofpenicillinbyAlexanderFlemingin1928[1]isthecornerstonediscoveryinthehistoryofthe‘antibioticera’.Still,theeffortsofPaulEhrlichandhisco-workerstoestablishasystematicscreeningapproachfordiscoveryofantimicrobialstookplacemuchearlierandintroducedthe‘magicbullet’Salvarsan[2,3].Salvarsanremainedthemostpopulouslyprescribeddrugagainstsyphilistillthefirstuseofpenicillinin1941[3,4].Prontosilasthefirstsulfadrugwasnextdiscoveredbytheuseofsameapproach[5]andfollowedbydiscoveryofstreptomycinwhichwasthefirstantibioticusedforthetreatmentoftuberculosis[6].In1945,thefungusCephalosporiumacremoniumwasshowntopro-ducean‘‘antibioticprinciple”effectiveagainststaphylococcal,streptococcalinfections,typhoidfeverandbrucellosis[7].Lateron,theprinciplewasdemonstratedtorepresentagroupofnaturalcompoundscalledcephalosporins,andN-phenylacetylderivativeofcephalosporinCbeingthemosteffectiveagainstStaphylococcusaureus[8,9].Theseinvestigationsledtotheproductionofnewgen-erationcephalosporincompou