MCB204LECTURENOTES4
ANTIBIOTICSANDCHEMOTHERAPEUTICAGENTS
HistoricalBackground
Theoutbreakofaninfectionortheclinicalmanifestationofmicrobialdiseasesindicatestheinabilityoftheh
ost'sdefencemechanismtoovercometheinfectingorganism.Chemicalsordrugsareoftenadministeredto
selectivelykilloraidinthekillingofsuchpathogenicorganisms,soastoreversethedangerousdiseasestateo
fthebody.Thispractiseofsystematicadministrationofchemicalsordrugsinthetreatmentofmicrobialdise
ases(withverylowtoxicpotentialonthehostcells)isreferredtoasantimicrobialchemotherapyandsubst
ancesusedforthispurposearecalledChemotherapeuticAgents.
ProgressinantimicrobialchemotherapywasinitiatedinGermanybyPaulEhrlich(1907)whofirsts
ynthesizedanorganicarsenical-
arsphenamineandingeniouslydemonstrateditstherapeuticactivityagainstthespirochaetesthatcausessy
philis.In1935,Domagkdiscoveredandreportedthecurativeeffectofprontosil,areddyewhichisaforerunn
erofthesulphonamidesonstreptococcalinfections.Thesediscoveriesledtoanewerainantimicrobialche
motherapyandeventuallyrevolutionizedthetreatmentofinfectiousdiseases.
Theobservationthatanorganismcouldinhibitanotherisalmostasoldasmicrobiology.However,t
heantibioticerawasheraldedbythediscoveryofpenicillin,aproductofthefungusPenicilliumnotatumby
AlexanderFleming(1929),whofoundthatthissubstancewasactiveagainstawiderangeofpathogensbutw
asnottoxictomammaliancells.Earlierin1928,FleminghadobservedthatthesporesofP.notatumwhichby
chancecontaminatedoneofhiscultureplatespreventedthegrowthofstaphylococciwerebeingcultured.It
wasthemeritofFlorey,Chanandco-
workeratOxfordUniversitywhosuccessfullyextractedandconcentratedpenicillinfromculturefluidsand
eventuallydemonstrateditsunequalledpotencyasachemotherapeuticagent,thusmarkingthegoldenerao
fantibiotics.
Thediscoveryandisolationofactinomycinin1940andstreptomycinin1944byWaksmanandhisc
olleaguesinAmericasparkedoffworld-
, wideinterestsinthesesubstances.Tillthepresentday,thesearchforbetterandnewerchemotherapeuticage
ntshasbeenhighlyintensified.
ThetermchemotherapywascoinedbyEhrlichin1909followinghissuccessfuluseofhisagentwhic
hhedescribedas'magicbullet'becauseofitsselectivetoxicity.
Indeedchemotherapeuticagentsarecompoundsthatinhibitthegrowthofinfectingorganismsat
concentrationsthataretoleratedbythehost.Thisdefinitionoriginallyreferredtosuchcompoundswithanti
microbialpropertiesthatarechemicallysynthesized
Antibioticsontheotherhand,arechemicalsubstancesproducedbyvariousspeciesofmicroorganis
msthatalso,inverysmallconcentrations,inhibitthegrowthofotherorganisms.However,withtheadventof
syntheticmethodsandalsothediscoveriesofcompoundsfromhighereukaryoticorganisms(plantsinparti
cular)whichpossessantimicrobialproperties,thedefinitionofantibiotichasbeenmodified.Thetermanti
bioticsnowreferstosubstancesproducedbyamicroorganismorsimilarsubstancesproducedwhollyorpar
tiallybychemicalsynthesiswhichinlowconcentrationpossessantimicrobialproperties.Forinstance,chlo
ramphenicolwhichwasoriginallyproducedfromStreptomycesvenezuelae,isnowcompletelyandwholly
producedsynthetically.Penicillinsandcephalosporinsareotherexamplesofantibioticswhichhavebeenc
hemicallymodifiedtoimprovetheirpharmacokinetics,antibacterialspectrumandresistancetoinactivati
ngenzymesproducedbysomepathogenicorganisms.
Generally,antimicrobialagentsareeitherbacteriostaticorbacterial.Theformerreversiblyinhibit
microorganismsandrelyonthehosts'defensemechanismsforthefinaleradicationoftheinfectingorganis
mwhereasthelattershowirreversiblelethalactionontheirtargetorganisms.Someofthesechemotherapeut
icalagentsactonlyonspecificornarrowgroupoforganisms,actingforinstanceeitheraloneongram-
negative,8rani-
positivebacteriaormainlyonanaerobes.Theyaresaidtobenarrowspectrum.Otherswhichactonawideran
geoforganismsarecalledbroad,spectrumantimicrobialagents.
Antibioticsarenaturallywidespreadoccurringinthesoil,water,sewageandcompostwheretheyar
ebelievedtoplayasignificantroleinkeepingthemicrobialpopulationoftheseenvironmentsincheck.Anti
microbialagentsdifferintheirchemicalstructuresaswellasintheirmodeofactions.Somecommonantimic
robialagentsandtheirrepresentativesareshowninTable1.
ANTIBIOTICSANDCHEMOTHERAPEUTICAGENTS
HistoricalBackground
Theoutbreakofaninfectionortheclinicalmanifestationofmicrobialdiseasesindicatestheinabilityoftheh
ost'sdefencemechanismtoovercometheinfectingorganism.Chemicalsordrugsareoftenadministeredto
selectivelykilloraidinthekillingofsuchpathogenicorganisms,soastoreversethedangerousdiseasestateo
fthebody.Thispractiseofsystematicadministrationofchemicalsordrugsinthetreatmentofmicrobialdise
ases(withverylowtoxicpotentialonthehostcells)isreferredtoasantimicrobialchemotherapyandsubst
ancesusedforthispurposearecalledChemotherapeuticAgents.
ProgressinantimicrobialchemotherapywasinitiatedinGermanybyPaulEhrlich(1907)whofirsts
ynthesizedanorganicarsenical-
arsphenamineandingeniouslydemonstrateditstherapeuticactivityagainstthespirochaetesthatcausessy
philis.In1935,Domagkdiscoveredandreportedthecurativeeffectofprontosil,areddyewhichisaforerunn
erofthesulphonamidesonstreptococcalinfections.Thesediscoveriesledtoanewerainantimicrobialche
motherapyandeventuallyrevolutionizedthetreatmentofinfectiousdiseases.
Theobservationthatanorganismcouldinhibitanotherisalmostasoldasmicrobiology.However,t
heantibioticerawasheraldedbythediscoveryofpenicillin,aproductofthefungusPenicilliumnotatumby
AlexanderFleming(1929),whofoundthatthissubstancewasactiveagainstawiderangeofpathogensbutw
asnottoxictomammaliancells.Earlierin1928,FleminghadobservedthatthesporesofP.notatumwhichby
chancecontaminatedoneofhiscultureplatespreventedthegrowthofstaphylococciwerebeingcultured.It
wasthemeritofFlorey,Chanandco-
workeratOxfordUniversitywhosuccessfullyextractedandconcentratedpenicillinfromculturefluidsand
eventuallydemonstrateditsunequalledpotencyasachemotherapeuticagent,thusmarkingthegoldenerao
fantibiotics.
Thediscoveryandisolationofactinomycinin1940andstreptomycinin1944byWaksmanandhisc
olleaguesinAmericasparkedoffworld-
, wideinterestsinthesesubstances.Tillthepresentday,thesearchforbetterandnewerchemotherapeuticage
ntshasbeenhighlyintensified.
ThetermchemotherapywascoinedbyEhrlichin1909followinghissuccessfuluseofhisagentwhic
hhedescribedas'magicbullet'becauseofitsselectivetoxicity.
Indeedchemotherapeuticagentsarecompoundsthatinhibitthegrowthofinfectingorganismsat
concentrationsthataretoleratedbythehost.Thisdefinitionoriginallyreferredtosuchcompoundswithanti
microbialpropertiesthatarechemicallysynthesized
Antibioticsontheotherhand,arechemicalsubstancesproducedbyvariousspeciesofmicroorganis
msthatalso,inverysmallconcentrations,inhibitthegrowthofotherorganisms.However,withtheadventof
syntheticmethodsandalsothediscoveriesofcompoundsfromhighereukaryoticorganisms(plantsinparti
cular)whichpossessantimicrobialproperties,thedefinitionofantibiotichasbeenmodified.Thetermanti
bioticsnowreferstosubstancesproducedbyamicroorganismorsimilarsubstancesproducedwhollyorpar
tiallybychemicalsynthesiswhichinlowconcentrationpossessantimicrobialproperties.Forinstance,chlo
ramphenicolwhichwasoriginallyproducedfromStreptomycesvenezuelae,isnowcompletelyandwholly
producedsynthetically.Penicillinsandcephalosporinsareotherexamplesofantibioticswhichhavebeenc
hemicallymodifiedtoimprovetheirpharmacokinetics,antibacterialspectrumandresistancetoinactivati
ngenzymesproducedbysomepathogenicorganisms.
Generally,antimicrobialagentsareeitherbacteriostaticorbacterial.Theformerreversiblyinhibit
microorganismsandrelyonthehosts'defensemechanismsforthefinaleradicationoftheinfectingorganis
mwhereasthelattershowirreversiblelethalactionontheirtargetorganisms.Someofthesechemotherapeut
icalagentsactonlyonspecificornarrowgroupoforganisms,actingforinstanceeitheraloneongram-
negative,8rani-
positivebacteriaormainlyonanaerobes.Theyaresaidtobenarrowspectrum.Otherswhichactonawideran
geoforganismsarecalledbroad,spectrumantimicrobialagents.
Antibioticsarenaturallywidespreadoccurringinthesoil,water,sewageandcompostwheretheyar
ebelievedtoplayasignificantroleinkeepingthemicrobialpopulationoftheseenvironmentsincheck.Anti
microbialagentsdifferintheirchemicalstructuresaswellasintheirmodeofactions.Somecommonantimic
robialagentsandtheirrepresentativesareshowninTable1.
