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Letizia Brandi, Attilio Fabbretti, Claudio O. Gualerzi, Cynthia L. Pon, Letizi Brandi, Letizia Brandi...
Antibiotics - Targets, Mechanisms and Resistance
English · Hardback
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Description
Most of the antibiotics now in use have been discovered more or less by chance, and their mechanisms of action have only been elucidated after their discovery. To meet the medical need for next-generation antibiotics, a more rational approach to antibiotic development is clearly needed.Opening with a general introduction about antimicrobial drugs, their targets and the problem of antibiotic resistance, this reference systematically covers currently known antibiotic classes, their molecular mechanisms and the targets on which they act. Novel targets such as cell signaling networks, riboswitches and bacterial chaperones are covered here, alongside the latest information on the molecular mechanisms of current blockbuster antibiotics. With its broad overview of current and future antibacterial drug development, this unique reference is essential reading for anyone involved in the development and therapeutic application of novel antibiotics.
List of contents
PrefaceA CHEMIST'S SURVEY OF DIFFERENT ANTIBIOTIC CLASSESIntroductionAminoglycosidesBeta-LactamsLinear PeptidesCyclic PeptidesThiazolylpeptidesMacrolactonesAnsamycins-RifamycinsTetracyclinesOxazolidinonesLincosamidesPleuromutilinsQuinolonesAminocoumarinsANTIBACTERIAL DISCOVERY: PROBLEMS AND POSSIBILITIESIntroductionWhy Is Antibacterial Discovery Difficult? The ProblemsTarget Choice: EssentialityTarget Choice: ResistanceCell EntryScreening StrategiesNatural ProductsComputational Chemistry, Virtual Screening, Structure- and Fragment-Based Drug Design (SBDD and FBDD)ConclusionsIMPACT OF MICROBIAL NATURAL PRODUCTS ON ANTIBACTERIAL DRUG DISCOVERYIntroductionNatural Products for Drug DiscoveryMicrobial Natural ProductsThe Challenge of Finding Novel Antibiotics from New Natural SourcesWorkflow for Drug Discovery from Microbial Natural ProductsAntimicrobial Activities: Targets for ScreensNatural Products: A Continuing Source for InspirationGenome Mining in Natural Product DiscoveryConclusionsANTIBIOTICS AND RESISTANCE: A FATAL ATTRACTIONTo Be or Not To Be Resistant: Why and How Antibiotic Resistance Mechanisms Develop and Spread among BacteriaBacterial Resistance to Antibiotics by Enzymatic Degradation or ModificationAntibiotic Target Alteration: The Trick Exists and It Is in the GeneticsEfflux SystemsThe Case Stories of Intrinsic and Acquired ResistancesStrategies to Overcome ResistanceFITNESS COSTS OF ANTIBIOTIC RESISTANCEIntroductionMethods to Estimate FitnessFactors Affecting FitnessMechanisms and Dynamics Causing Persistence of Chromosomal and Plasmid-Borne Resistance DeterminantsINHIBITORS OF CELL-WALL SYNTHESISIntroductionMraY InhibitorsLipid II Targeting CompoundsBactoprenol PhosphateConclusionsINHIBITORS OF BACTERIAL CELL PARTITIONINGIntroductionBacterial Cell DivisionCell Division Proteins as Therapeutic TargetsStatus of FtsZ-Targeting Compounds: From Laboratory to ClinicConclusionTHE MEMBRANE AS A NOVEL TARGET SITE FOR ANTIBIOTICS TO KILL PERSISTING BACTERIAL PATHOGENSIntroductionThe Challenge of Treating Dormant InfectionsDiscovery Strategies to Prevent or Kill Dormant BacteriaWhy Targeting the Membrane Could Be a Suitable StrategyTarget Essentiality and SelectivityMultiple Modes of ActionsTherapeutic Use of Membrane-Damaging Agents against BiofilmsNew Approaches to Identifying Compounds That Kill Dormant BacteriaChallenges for Biofilm Control with Membrane-Active AgentsPotential for Membrane-Damaging Agents in TB DiseaseApplication to Treatment for Clostridium difficile InfectionIs Inhibition of Fatty Acid/Phospholipid Biosynthesis Also an Approach?Concluding RemarksBACTERIAL MEMBRANE, A KEY FOR CONTROLLING DRUG INFLUX AND EFFLUXIntroductionThe Mechanical BarrierCircumventing the Bacterial Membrane BarrierConclusionINTERFERENCE WITH BACTERIAL CELL-TO-CELL CHEMICAL SIGNALING IN DEVELOPMENT OF NEW ANTI-INFECTIVESIntroductionTwo-Component Systems (TCSs) as Potential Anti-Infective TargetsWalK/WalR and MtrB/MtrA: Case Studies of Essential TCSs as Drug TargetsTargeting Nonessential TCSNon-TCSs Targeting Biofilm Formation and Quorum Sensing in Pseudomonas spp.ConclusionsRECENT DEVELOPMENTS IN INHIBITORS OF BACTERIAL TYPE IIA TOPOISOMERASESIntroductionDNA-Gate InhibitorsATPase-Domain InhibitorsSimocyclinones, Gyramides, and Other Miscellaneous InhibitorsConclusions and PerspectivesANTIBIOTICS TARGETING BACTERIAL RNA POLYMERASEIntroductionAntibiotics Blocking Nascent RNA ExtensionAntibiotics Targeting RNAP Active CenterAntibiotics Blocking Promoter Complex FormationInhibitors Hindering Sigma-Core InteractionsInhibitors with Unknown Mechanisms and Binding SitesConclusions and PerspectivesINHIBITORS TARGETING RIBOSWITCHES AND RIBOZYMESIntroductionRiboswitches as Antibacterial Drug TargetsRibozymes as Antibacterial Drug TargetsConcluding Remarks and Future PerspectivesTARGETING RIBONUCLEASE PIntroductionTargeting RNase P with Antisense StrategiesAminoglycosidesPeptidyltransferase InhibitorsSubstrate Masking by Synthetic InhibitorsPeculiar Behavior of Macrolides on Bacterial RNase PAntipsoriatic CompoundsConclusions and Future PerspectivesINVOLVEMENT OF RIBOSOME BIOGENESIS IN ANTIBIOTIC FUNCTION, ACQUIRED RESISTANCE, AND FUTURE OPPORTUNITIES IN DRUG DISCOVERYIntroductionRibosome BiogenesisMethyltransferasesMethyltransferase Integration into the Ribosome Biogenesis PathwayRibosome Biogenesis Factors, Virulence, and Vaccine DevelopmentAMINOACYL-Trna Synthetase InhibitorsIntroductionEnzymatic Mechanism of Action of aaRSaaRS InhibitorsConsiderations for the Development of aaRS InhibitorsConclusionsANTIBIOTICS TARGETING TRANSLATION INITIATION IN PROKARYOTESIntroductionMechanism of Translation InitiationInhibitors of Folate MetabolismMethionyl-tRNA FormyltransferaseInhibitors of Peptide DeformylaseInhibitors of Translation Initiation Factor IF2ppGpp Analogs as Potential Translation Initiation InhibitorsTranslation Initiation Inhibitors Targeting the P-SiteINHIBITORS OF BACTERIAL ELONGATION FACTOR EF-TuIntroductionEnacyloxinsKirromycinPulvomycinGE2270AAMINOGLYCOSIDE ANTIBIOTICS: STRUCTURAL DECODING OF INHIBITORS TARGETING THE RIBOSOMAL DECODING A SITEIntroductionChemical Structures of AminoglycosidesSecondary Structures of the Target A SitesOverview of the Molecular Recognition of Aminoglycosides by the Bacterial A SiteRole of Ring I: Specific Recognition of the Binding PocketRole of Ring II (2-DOS Ring): Locking the A-Site Switch in the "On" StateDual Roles of Extra Rings: Improving the Binding Affinity and Eluding Defense MechanismsBinding of Semisynthetic Aminoglycosides to the Bacterial A SitesBinding of Aminoglycosides to the Antibiotic-Resistant Bacterial Mutant and Protozoal Cytoplasmic A SitesBinding of Aminoglycosides to the Human A SitesOther Aminoglycosides Targeting the A Site but with Different Modes of ActionAminoglycosides that Do Not Target the A SiteNonaminoglycoside Antibiotic Targeting the A SiteConclusionsPEPTIDYLTRANSFERASE INHIBITORS OF THE BACTERIAL RIBOSOMEPeptide Bond Formation and Its Inhibition by AntibioticsPuromycin Mimics the CCA-End of tRNAsChloramphenicols Inhibit A-tRNA Binding in an Amino-Acid-Specific MannerThe Oxazolidinones Bind at the A-Site of the PTCLincosamide Action at the A-Site of the PTCBlasticidin S Mimics the CCA-End of the P-tRNA at the PTCSparsomycin Prevents A-Site and Stimulates P-Site tRNA BindingPleuromutilins Overlap A- and P-Sites at the PTCThe Synergeistic Action of Streptogramins at the PTCFuture PerspectivesANTIBIOTICS INHIBITING THE TRANSLOCATION STEP OF PROTEIN ELONGATION ON THE RIBOSOMEIntroductionTranslocation: OverviewAntibiotics Inhibiting TranslocationAntibiotics Inhibiting Translocation in EukaryotesAntibiotics Inhibiting Ribosome Recycling in BacteriaPerspectiveANTIBIOTICS AT THE RIBOSOMAL EXIT TUNNEL - SELECTRED STRUCTURAL ASPECTSIntroductionThe Multifunctional TunnelA Binding Pocket within the Multifunctional TunnelRemotely ResistanceResistance WarfareSynergismPathogen and "Patiens" ModelsConclusion and Future ConsiderationsTARGETING HSP70 TO FIGHT CANCER AND BAG BUGS: ONE AND THE SAME BATTLE?A Novel Target: The Bacterial Chaperone HSP70An In vivo Screening for Compounds Targeting DnaKDrugging HSP70Cooperation between the Bacterial Molecular Chaperones DnaK and HtpGDrugging HSP90Index
About the author
Claudio Gualerzi is full professor of Molecular Biology at the University of Camerino (Italy) and member of the EMBO. Following his studies at the University of Rome-La Sapienza and a postdoctoral period at the University of Pennsylvania (USA), he served as research group leader at the Max-Planck-Institute for Molecular Genetics in Berlin (Germany). He was consultant for the Lepetit Research Center in Gerenzano (Italy) and has received numerous awards and honorary lectureships, including the research prize of the Alexander von Humboldt foundation for his work on ribosome function and the discovery of novel antibiotics.
Attilio Fabbretti completed his doctoral studies at the University of Camerino (Italy) where he is now a research associate in the laboratory of Molecular Biology. He received the prize of the Italian Society for General Microbiology and Microbial Biotechnology for the best PhD thesis in 2007.
Letizia Brandi received her doctoral degree from the University of Catania after performing her thesis work at the University of Camerino, Italy. She served a postdoctoral period at the University of Montana (Missoula, USA) and worked as a senior scientist at Biosearch Italia, spa and Vicuron Pharmaceuticals (Gerenzano, Italy), before joining the laboratory of Molecular Biology at the University of Camerino where she is now a research associate.
Cynthia Pon received her PhD from Rutgers the State University (USA). Following post-doctoral periods at the University of Pennsylvania and Hunter College of the City University of New York, she worked at the Max-Planck-Institute for Molecular Genetics in Berlin (Germany) before becoming full professor of Molecular and Microbial Genetics at the University of Camerino (Italy). Her work has focused on the mechanism of protein synthesis, global responses in bacteria and action of antibiotics.
Summary
Most of the antibiotics now in use have been discovered more or less by chance, and their mechanisms of action have only been elucidated after their discovery. To meet the medical need for next-generation antibiotics, a more rational approach to antibiotic development is clearly needed.
Opening with a general introduction about antimicrobial drugs, their targets and the problem of antibiotic resistance, this reference systematically covers currently known antibiotic classes, their molecular mechanisms and the targets on which they act. Novel targets such as cell signaling networks, riboswitches and bacterial chaperones are covered here, alongside the latest information on the molecular mechanisms of current blockbuster antibiotics.
With its broad overview of current and future antibacterial drug development, this unique reference is essential reading for anyone involved in the development and therapeutic application of novel antibiotics.
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