Antibiotics: Targets, Mechanisms and Resistance

575 Pages·2013·5.82 MB·English

by  Claudio O. Gualerzi

Edited by Claudio O. Gualerzi, Letizia Brandi,
Attilio Fabbretti, Cynthia L. Pon
Antibiotics
Targets, Mechanisms and Resistance

Editedby
ClaudioO.Gualerzi,LetiziaBrandi,
AttilioFabbretti,andCynthiaL.Pon
Antibiotics
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Edited by Claudio O. Gualerzi, Letizia Brandi,
Attilio Fabbretti, and Cynthia L. Pon
Antibiotics
Targets, Mechanisms and Resistance
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V
Contents
Preface XVII
ListofContributors XIX
1 AChemist’sSurveyofDifferentAntibioticClasses 1
SoniaIlariaMaffioli
1.1 Introduction 1
1.2 Aminoglycosides 1
1.3 β-Lactams 3
1.4 LinearPeptides 4
1.4.1 Glycopeptides-Dalbaheptides 4
1.4.2 Lantibiotics 6
1.5 CyclicPeptides 8
1.6 Thiazolylpeptides 11
1.7 Macrolactones 13
1.7.1 Macrolides 13
1.7.2 Difimicin 15
1.8 Ansamycins–Rifamycins 15
1.9 Tetracyclines 16
1.10 Oxazolidinones 16
1.11 Lincosamides 18
1.12 Pleuromutilins 18
1.13 Quinolones 19
1.14 Aminocoumarins 19
References 20
2 AntibacterialDiscovery:ProblemsandPossibilities 23
LynnL.Silver
2.1 Introduction 23
2.2 WhyIsAntibacterialDiscoveryDifficult?TheProblems 24
2.3 TargetChoice:Essentiality 24
2.4 TargetChoice:Resistance 26
2.5 CellEntry 31
VI Contents
2.6 ScreeningStrategies 32
2.6.1 EmpiricalScreens 32
2.6.2 PhenotypicWhole-CellScreens 34
2.6.3 InVitroScreensforSingle-TargetInhibitors 37
2.6.4 ChemicalstoScreen 38
2.6.4.1 ChemicalCollections 38
2.7 NaturalProducts 40
2.8 ComputationalChemistry,VirtualScreening,Structure-and
Fragment-BasedDrugDesign(SBDDandFBDD) 42
2.9 Conclusions 45
References 46
3 ImpactofMicrobialNaturalProductsonAntibacterialDrug
Discovery 53
GabriellaMolinari
3.1 Introduction 53
3.2 NaturalProductsforDrugDiscovery 54
3.3 MicrobialNaturalProducts 56
3.4 TheChallengeofFindingNovelAntibioticsfromNewNatural
Sources 59
3.5 WorkflowforDrugDiscoveryfromMicrobialNaturalProducts 60
3.6 AntimicrobialActivities:TargetsforScreens 63
3.7 NaturalProducts:AContinuingSourceforInspiration 65
3.8 GenomeMininginNaturalProductDiscovery 66
3.9 Conclusions 67
References 68
4 AntibioticsandResistance:AFatalAttraction 73
GiuseppeGalloandAnnaMariaPuglia
4.1 ToBeorNottoBeResistant:WhyandHowAntibioticResistance
MechanismsDevelopandSpreadamongBacteria 73
4.1.1 HorizontalandVerticalTransmissionofResistanceGenes 74
4.2 BacterialResistancetoAntibioticsbyEnzymaticDegradationor
Modification 79
4.2.1 AntibioticResistancebyHydrolyticEnzymes 80
4.2.1.1 β-Lactamases 81
4.2.1.2 MacrolideEsterases 81
4.2.1.3 Epoxidases 81
4.2.1.4 Proteases 83
4.2.2 AntibioticTransferasesPreventTargetRecognition 83
4.2.2.1 Acyltransfer 83
4.2.2.2 Phosphotransferases 84
4.2.2.3 Nucleotidyltransferases 85
4.2.2.4 ADP-Ribosyltransferases 85
4.2.2.5 Glycosyltransferases 85
Contents VII
4.2.3 RedoxEnzymes 86
4.3 AntibioticTargetAlteration:TheTrickExistsandItIsinthe
Genetics 86
4.3.1 Low-AffinityHomologousGenes 86
4.3.1.1 RifamycinLow-AffinityRpoB 87
4.3.1.2 MutatedGenesConferringResistancetoQuinolone,Fluoroquinolone
andAminocoumarins 87
4.3.1.3 PBP2a:ALow-AffinityPenicillin-BindingProtein 87
4.3.1.4 DihydropteroateSynthasesNotInhibitedbySulfonamide 88
4.3.2 ChemicalModificationofAntibioticTarget 88
4.3.2.1 23SrRNAModification 88
4.3.2.2 16SrRNAModification 88
4.3.2.3 ReprogrammingChemicalCompositionofaBacterialCell-Wall
Precursor 89
4.3.3 RibosomalProtectionandTetracyclineResistance 89
4.3.4 ChromosomalMutationsinGenesRequiredforMembrane
PhospholipidMetabolism:LipopeptideResistance 91
4.3.5 CovalentModificationsonLipopolysaccharideCoreConferring
PolymixineResistance 92
4.4 EffluxSystems 92
4.4.1 TheATP-BindingCassette(ABC)Superfamily 94
4.4.2 TheMajorFacilitatorSuperfamily(MSF) 94
4.4.3 TheSmallMultidrug-ResistanceFamily(SMR) 96
4.4.4 TheResistance-Nodulation-Division(RND)Superfamily 96
4.4.5 TheMultidrugandToxicCompoundExtrusion(MATE)Family 97
4.5 TheCaseStoriesofIntrinsicandAcquiredResistances 98
4.5.1 β-LactamResistomeof P.aeruginosa:IntrinsicResistanceIsGenetically
Determined 98
4.5.2 AcquiredAntibioticResistanceinS.aureus 98
4.5.2.1 AcquiredResistancetoβ-LactamsandGlycopeptides 99
4.5.2.2 AcquiredResistancetoFluoroquinolones 100
4.6 StrategiestoOvercomeResistance 100
References 101
5 FitnessCostsofAntibioticResistance 109
PietroAlifano
5.1 Introduction 109
5.2 MethodstoEstimateFitness 110
5.2.1 ExperimentalMethods 110
5.2.2 EpidemiologicalMethods 111
5.3 FactorsAffectingFitness 112
5.3.1 GeneticNatureoftheResistantDeterminant 112
5.3.2 ExpressionoftheAntibiotic-ResistanceDeterminant 118
5.3.3 MicrobialCellPhysiology,Metabolism,andLifestyle 119
5.3.4 GeneticBackgroundoftheAntibiotic-ResistantMutant 120
VIII Contents
5.4 MechanismsandDynamicsCausingPersistenceofChromosomaland
Plasmid-BorneResistanceDeterminants 121
5.4.1 CompensatoryGeneticMechanismsThatRestoreorImproveFitness
withoutLossofResistance 121
5.4.2 LinkedSelectionandSegregationStabilityofResistance
Determinants 126
5.4.3 ReacquisitionofAntimicrobialResistance 127
References 128
6 InhibitorsofCell-WallSynthesis 133
StefanoDonadioandMargheritaSosio
6.1 Introduction 133
6.2 MraYInhibitors 134
6.3 LipidIITargetingCompounds 137
6.3.1 Glycopeptides 137
6.3.2 Lantibiotics 139
6.3.3 RamoplaninandEnduracidin 143
6.3.4 OtherCompounds 143
6.4 BactoprenolPhosphate 145
6.5 Conclusions 146
Acknowledgments 146
References 147
7 InhibitorsofBacterialCellPartitioning 151
BhavyaJindal,AnusriBhattacharya,andDulalPanda
7.1 Introduction 151
7.2 BacterialCellDivision 152
7.2.1 FilamentousTemperature-SensitiveZ(FtsZ) 152
7.2.2 StructureandAssemblyPropertiesofFtsZ 152
7.2.3 Z-Ring:ADynamicStructureThatDrivesBacterialCellDivision 153
7.2.4 ProteinsRegulatingFtsZAssembly 155
7.2.5 ProteinsInvolvedinSeptumFormation 156
7.2.6 RoleofOtherCytoskeletonProteinsinBacterialCellDivision 157
7.3 CellDivisionProteinsasTherapeuticTargets 158
7.3.1 FtsZasaTherapeuticTarget 158
7.3.1.1 IdentificationofFtsZ-TargetingAntibacterialAgents 158
7.3.1.2 FtsZInhibitors 161
7.3.2 OtherCellDivisionProteinsasTherapeuticTargets 170
7.4 StatusofFtsZ-TargetingCompounds:FromLaboratorytoClinic 172
7.5 Conclusion 173
Acknowledgment 173
Abbreviations 173
References 174