Chemistry of Antibiotics and Related Drugs

276 Pages·2022·15.861 MB·English

by  Mrinal K. Bhattacharjee

Mrinal K. Bhattacharjee
Chemistry
of Antibiotics
and Related
Drugs
Second Edition
Chemistry of Antibiotics and Related Drugs
Mrinal K. Bhattacharjee
Chemistry of Antibiotics
and Related Drugs
Second Edition
MrinalK.Bhattacharjee
DepartmentofChemistryandBiochemistry
LongIslandUniversity
Brooklyn,NY,USA
ISBN978-3-031-07581-0 ISBN978-3-031-07582-7 (eBook)
https://doi.org/10.1007/978-3-031-07582-7
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Preface
Millions of lives have been saved by antibiotics since they were first discovered
more than 90 years ago. This book discusses the various classes of antibiotics and
their mechanisms of action. For the first few decades, antibiotics had a remarkable
success, encouraged by which in 1969, the then-US Surgeon General, William
Stewart testified before Congress that it was “time to close the book on infectious
disease.”Todayweknowhowprematurethatstatementwas.Today,morethanfive
decades later, infectiousdiseasestillremainstheleadingcause ofdeath worldwide
and ranks among the top ten causes of death in the USA. The main reason for all
theseisthatbacteriaareincreasinglybecomingresistanttoantibiotics.Mechanisms
bywhichbacteriadevelopresistancetoantibioticsarealsodiscussedhere.Because
oftheincreasingantimicrobialresistance,itisofutmostimportancetodiscovernew
antibiotics.Alternativestrategiesfordiscoveringnewantibioticsarepresented.The
World Health Organization has recognized the threat of growing antimicrobial
resistance and has adopted a Global Action Plan to combat the threat. This plan
andsimilarplansofmembercountriesaswellasStewardshipProgramsadoptedby
agenciesatlocallevelsarealsodiscussed.
This book has been written keeping the student in mind. The main focus is to
explain how antibiotics work in curing infectious diseases and how resistance
develops to the antibiotics such that they do not work anymore. A background in
Biochemistry is needed to understand the mechanism of action of the antibiotics.
However,anybackgroundinformationthatisneededisdiscussedinthebook.Soit
willnotbenecessaryforthestudenttoconsultanyseparatebiochemistrytextbook,
orregisterforaseparatecourseinbiochemistry,inordertounderstandthetheoryof
antibiotics.However,thediscussionofbiochemistryinthisbookisnotmeanttobe
complete.Theonlyinformationpresentediswhatisrelevanttotheunderstandingof
antibiotics.
Therearemanyotherimportantaspectsofantibioticsthatarestudiedbydoctors,
pharmacists, and scientists but are beyond the scope of this book. Some of these
aspects are briefly mentioned here but will not be discussed in much detail in the
book.
vii
viii Preface
1. Dosage, formulation, bioavailability, and biostability are important aspects for
effective use of antibiotics. These ensure that the antibiotic will be delivered
specifically to diseased site in the right amount and for the required duration.
Dose depends on how much of the antibiotic is absorbed from the digestive
system,howstableitis,howmuchentersthecells,thedistributionofthedrugin
varioustissues,andmanyotherfactors.However,discussionsoftheseaspectsare
beyondthescopeofthisbook.
2. Allantibioticsdonotworkforallinfections.Also,antibioticshavevariousside
effects and may interact with other drugs to give unwanted effects. Information
neededtodecideaboutwhichantibiotictoprescribeforwhichinfectionisbeyond
thescopeofthisbook.
Allantibioticswillbereferredtoherebytheircommonnamessuchaspenicillin,
tetracycline, erythromycin, etc., even though many of these antibiotics have other
brand names given by the manufacturers. There are also various derivatives with
alteredbutsimilaractivitiesformanyoftheseantibiotics.Notallofthesenamesare
included in this book. All antibiotics will also have a systematic name based on
IUPACnomenclatureoforganiccompounds.Thosenameswillbementionedforthe
simplemoleculesbutnotforthosewithcomplexstructures.
Brooklyn,NY,USA MrinalK.Bhattacharjee
April2022
Contents
1 IntroductiontoAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 DefinitionofAntibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 HistoryofAntibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3 TheIdealAntibiotic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.4 SourcesofAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.5 DiscoveryofModernAntibiotics. . . . . . . . . . . . . . . . . . . . . . . 7
1.6 ClassificationofAntibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.7 BackgroundBiochemistryInformation. . . . . . . . . . . . . . . . . . . 13
1.7.1 Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.7.2 EnzymeInhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.7.3 EnzymeMechanisms . . . . . . . . . . . . . . . . . . . . . . . . 15
1.7.4 MetabolismandMetabolicPathways . . . . . . . . . . . . . 18
1.7.5 ThermodynamicsofMetabolicPathways . . . . . . . . . . 19
1.7.6 High-EnergyCompounds. . . . . . . . . . . . . . . . . . . . . 21
1.7.7 MetabolicallyIrreversibleandNear-Equilibrium
Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.7.8 MembraneTransport . . . . . . . . . . . . . . . . . . . . . . . . 26
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2 DevelopmentofResistancetoAntibiotics . . . . . . . . . . . . . . . . . . . . 29
2.1 AntibioticsAreNoLongerConsideredtoBeMiracleDrugs. . . 29
2.2 DetectionofAntibioticResistance. . . . . . . . . . . . . . . . . . . . . . 30
2.3 ClassificationofAntibioticResistance. . . . . . . . . . . . . . . . . . . 31
2.4 ResistanceDevelopmentbyPointMutations. . . . . . . . . . . . . . . 31
2.5 SelectionforResistance . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . 33
2.6 ResistanceDevelopmentbyResistanceGeneAcquisition . . . .. 35
2.7 MechanismofAntimicrobialResistance. . . . . . . . . . . . . . . . . . 38
2.8 SyntheticAntibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.9 AlternativeApproachesforStudyingAntibiotics. . . . . . . . . . . . 42
2.10 AntibioticUseinAnimals. . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
ix
x Contents
2.10.1 TherapeuticUse . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.10.2 SubtherapeuticUse. . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.11 PreventionofAntibioticResistanceDevelopment. . . . . . . . . . . 50
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3 AntibioticsThatInhibitCellWallSynthesis . . . . . . . . . . . . . . . . . . 55
3.1 BackgroundBiochemistryInformation. . . . . . . . . . . . . . . . . . . 55
3.1.1 Carbohydrates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.1.2 MolecularStructureofBacterialCellWall. . . . . . . . . 58
3.2 BiosynthesisofPeptidoglycanoftheCellWall. . . . . . . . . . . . . 58
3.2.1 Stage1:TheCytosolicPhaseofSynthesis. . . . . . . . . 59
3.2.2 Stage2:TheMembranePhaseofSynthesis. . . . . . . . 62
3.2.3 Stage3:TheCellWallPhaseofSynthesis. . . . . . . . . 64
3.3 AntibioticsThatInhibitCellWallBiosynthesis . . . . . . . . . . . . . 67
3.3.1 AntibioticsTargetingtheCytosolicPhase
ofSynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.3.2 AntibioticsTargetingtheCellWallPhase
ofSynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.3.3 AntibioticsTargetingtheMembranePhase
ofSynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
3.3.4 Teixobactin,ANewlyDiscoveredAntibiotic. . . . . . . 102
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 Antimetabolites:AntibioticsThatInhibitNucleotideSynthesis . . .. 109
4.1 Antimetabolites . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. 109
4.2 BackgroundBiochemistryInformation:FolicAcid . . . . . . . . . . 110
4.3 AntibioticsThatInhibitFolateMetabolism . . . . . . . . . . . . . . . . 112
4.3.1 SulfaDrugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
4.3.2 MechanismofActionofSulfonamides. . . . . . . . . . . 113
4.3.3 NegativeAspectsofSulfonamides. . . . . . . . . . . . . . . 115
4.3.4 Non-sulfonamideAntimetabolitesofFolicAcid . . . .. 115
4.3.5 AntimetabolitesasDihydrofolateReductase
(DHFR)Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . 117
4.3.6 AntimetabolitesasAntibacterial,Antimalarial,
andAnticancerAgents. . . . . . . . . . . . . . . . . . . . . . . 118
4.3.7 ThymidylateSynthaseInhibitor:5-Fluorouracil . . . .. 120
4.3.8 OtherAntimetabolites:Azaserineand
Diazo-Oxo-Norleucine. . . . . . . . . . . . . . . . . . . . . . . 122
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5 AntibioticsThatInhibitNucleicAcidSynthesis . . . . . . . . . . . . . . . . 125
5.1 BackgroundBiochemistryInformation. . . . . . . . . . . . . . . . . . . 125
5.1.1 StructureofNucleotides. . . . . . . . . . . . . . . . . . . . . . 125
5.1.2 Watson–CrickModelofDNA. . . . . . . . . . . . . . . . . . 126
5.1.3 SuperhelicalStructureofDNA. . . . . . . . . . . . . . . . . 128
Contents xi
5.1.4 DNAReplication. . . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.2 IntercalatorsasAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
5.3 InhibitorsofDNAGyrase:Quinolones. . . . . . . . . . . . . . . . . . . 132
5.3.1 MechanismofResistancetoQuinolones. . . . . . . . .. 136
5.4 NitroheterocyclicAromaticCompoundsasAntibiotics. . . . . . . 138
5.4.1 Nitroimidazoles:AntibioticsThatCleaveDNA . . . .. 138
5.4.2 Nitrofurans:MultiplePossibleMechanisms
ofAction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5.5 RNASynthesis:BackgroundBiochemistryInformation. . . . . . . 142
5.6 Rifamycins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
5.7 ActinomycinD(Dactinomycin). . . . . . . . . . . . . . . . . . . . . . . . 145
5.8 Fidaxomicin:ANewAntibioticwithaNewTarget. . . . . . . . . . 145
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
6 AntibioticsThatInhibitProteinSynthesis . . . . . . . . . . . . . . . . . . . . 149
6.1 ProteinSynthesis:BackgroundBiochemistryInformation . . . .. 149
6.2 AntibioticsThatInhibitProteinSynthesis. . . . . . . . . . . . . . . . . 155
6.2.1 Puromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
6.2.2 Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
6.2.3 ResistancetoAminoglycosides. . . . . . . . . . . . . . . . . 159
6.2.4 Tetracyclines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
6.2.5 Chloramphenicol. . . . . . . . . . . . . . . . . . . . . . . . . . . 163
6.2.6 TheMLSGroupofAntibiotics. . . . . . . . . . . . . . . . . 165
6.2.7 TwoTrulyNewAntibiotics . . . . .. . . . .. . . .. . . . .. 168
6.2.8 ProteinSynthesisAntibioticswithUnusual
MechanismsofAction . . . . . . . . . . . . . . . . . . . . . . . 170
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
7 AntibioticsThatAffecttheMembraneandOtherStructural
Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
7.1 BackgroundBiochemistryInformation. . . . . . . . . . . . . . . . . . . 179
7.1.1 FunctionofBiologicalMembranes. . . . . . . . . . . . . . 179
7.1.2 CompositionoftheMembrane . . . . . . . . . . . . . . . . . 180
7.2 InhibitionofBacterialMembraneFunction . . . . . . . . . . . . . . . . 183
7.2.1 AntisepticsandDisinfectantsThatDisrupt
MicrobialCellMembrane. . . . . . . . . . . . . . . . . . . . . 183
7.2.2 AntibioticsthatFunctionbyDisrupting
MicrobialCellMembrane. . . . . . . . . . . . . . . . . . . . . 186
7.3 AntibioticsAffectingOtherStructuralTargets. . . . . . . . . . . . . . 198
7.3.1 Triclosan,TheAntibioticThatInhibitsFatty
AcidSynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
7.3.2 Isoniazid:AntibioticAgainstTuberculosis . . . . . . . . . 199
7.3.3 AntibioticsTargetingFtsZ,TheCellDivision
Protein . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . 200
References. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200