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Biogenesisofantibiotics—viewingitshistoryandglimpsesofthefutureJ.Spížek1&K.Sigler1&T.Řezanka1&A.Demain2Received:9March2016/Accepted:2May2016/Publishedonline:18May2016#InstituteofMicrobiology,AcademyofSciencesoftheCzechRepublic,v.v.i.2016AbstractThisreviewaimsatcomparingsomehistoricaldatawiththecurrentsituationinthestudyofbiogenesisofnaturalcompounds,antibioticsinthefirstplace.Biogenesisoftetracyclinesandcycloheximideandrelat-edcompoundsservesasexample.Examplesofmolecu-larbiologicalandbioinformaticsmethodsusedinthestudyofantibioticbiogenesisaredescribedbothintermsofitshistoricalaspectsandthecurrentknowledge.IntroductionAlllivingorganismsproduceaplethoraofbiologicallyactivecompounds.Inthisreview,wewillconcentrateonso-calledsecondarymetabolites,i.e.,compoundsthatarenotabsolutelyessentialfortheirproducers;nonpro-ducingmutantsexistthatliveandmultiplywithoutproducingsuchcompounds.Antibioticsbelongtothisgroupofcompounds.Althoughthenumbersareappar-entlyonlyroughestimates,amongeubacteria,actinobacteriaseemtobethemostefficientantibioticproducersfollowedbyfungi.Intotal,microorganismsproducemorethan40,000antibiotics,whereasBhigher^organismsincludingplantsandevenanimalsproducesome25,000antibiotics(seeTable1).Thetotalestimatednumberofnaturalantibioticsvariesfromabout66,060to70,560.Thenumberofsemisyntheticandsyntheticcompoundsderivedfromthemcanbeestimatedas100,000orevenmore.Outofthishighnumberofcompounds,onlyabouthundredsareusedinclinicalpractice.Thenumbersarehighlyapproximateandtheactuallistofantibioticsproducedbymicroorganismswouldbeprobablymuchhigher.Inanycase,thenumbersofnat-uralantibioticsareestimatedtobeoftheorderof104,totalantibioticsincludingsemisyntheticcompoundsamountto105,whereasonlyroughly102areusedinclinicalpractice.Mostapplicableantibioticsweredis-coveredandbroughttomarketduringtheso-calledGoldenAgeasdemonstratedbyHopwood(2007)(Fig.1).AccordingtoBibbandHesketh(2009)actinomy-cetes,thefamilytowhichthestreptomycetesbelongisresponsiblefortheproductionofovertwo-thirdsofknownantibiotics.Thelistpresentedhereisonlyintendedtoreflectproportionsofthecompoundspro-ducedbydifferentmicroorganisms.Eachsecondaryme-taboliteincludingantibioticsisformedfromproductsofprimarymetabolism.ThechemicalstructureofaDedicatedtothelateZdenkoVaněk,aneminentscientistanddearfriend.Motto:SirDavidA.Hopwood:Zdenkopassedaway:BItisindeedtheendofanera.^*J.Spíž[e-mail]1InstituteofMicrobiologyv.v.i,AcademyofSciencesoftheCzechRepublic,Vídeňská1083,14220Prague4,CzechRepublic2ResearchInstituteforScientistsEmeriti(RISE),DrewUniversity,Madison,NJ,USAFoliaMicrobiol(2016)61:347–358DOI10.1007/s12223-016-0462-ysecondarymetaboliteusuallyindicateswhichbiosynthet-icpathwayisinvolvedinitsproduction.Thediversityofsecondarymetabolitesisenormous,butinspiteofthis,theirbiosynthesisisinprinciplebasedonvaria-tionsofonlyseveralessentialpathways,viz.synthesisofpolyketides,peptidesorpolypeptides,terpenesorste-rols,etc.,ortheircombinations.Tetracyclines,cyclohex-imides,anderythromycinsmayserveasexamplesofpolyketideantibiotics.Anumberofreviewarticlesonbiogenesisofantibi-oticsandantibioticproductionhaverelativelyrecentlybeenpublishedincludingpapersbyDemainandSanchez(2009),BibbandHesketh(2009),Leeetal.(2009)andDemainandSpizek(2012).Othervaluable,indeedhistoricalreviewswerepublishedinthenineties(Hopwoodetal.1995;DoullandVining1995;ChampnessandChater1994;ChaterandBibb1997).ThecurrentsituationhasrecentlybeendescribedinexcellentreviewarticlespublishedinNatureChemicalBiology(FocusonBiosynthesis,Volume11,No.9,Sept2015).Itisclearthattheimprovedtoolsandpro-ceduresmakeitpossibletoobtainnewinformationonthepromisingapplicationsofnaturalproductsbiosynthesis(Spížeketal.2010).Thesecompounds,es-peciallyantibiotics,foundimportantapplicationsinhu-manandveterinarymedicine.Theenzymescatalyzingtheirbiosynthesisapparentlyplayacrucialrole.Specificityofindividualenzymesdetermineswhatbuild-ingblocksleadingtotheformationofsecondarymetab-oliteswillbeincorporatedandhowtheywillbemodi-fied.Theinformationobtainedcanbeusedtopredicttheresultantcompounds.Geneclusterscodingforaparticu-larmoleculecannowbequicklyidentifiedfromcompar-isonswiththousandsofgenomesidentifiedsofar.Atpresent,informatictoolscanbeusedtopredictwhatmoleculeswillbeproduced.ThemassiveinformationongenomicdataindicateswhatadditionalclustersmayTable1MainantibioticproducersMicroorganismsNumberofproducedantibioticsProducingorganismActinobacteria14,500Streptomycessp.11,000Otheractinobacteria3400EubacteriaMyxobacteria450Cyanobacteria400Otherbacteria800FungiMicroscopicfungi(Aspergillus,Penicillium)9000Basidiomycetes2900Otherfungiincludingyeasts,slimemolds,etc.110Totalmicroorganisms42,560HigherorganismsHigherplants15,000–16,000Lowerplantsincludingalgae,mosses,andlichens1500–2000Productsofterrestrialanimals1000–2000Marineproducts(plantsandanimals)6000–8000Total23,500–28,000Totalestimatednumberofnaturalantibiotics66,060–70,560FromBerdy2015Fig.1Discoveryofimportantantibioticandothernaturalproductsovertheyears.Boldtypeindicatesactinomycete