Details

Antibiotics


Antibiotics

Targets, Mechanisms and Resistance
1. Aufl.

von: Claudio O. Gualerzi, Letizia Brandi, Attilio Fabbretti, Cynthia L. Pon

160,99 €

Verlag: Wiley-VCH
Format: EPUB
Veröffentl.: 05.09.2013
ISBN/EAN: 9783527659708
Sprache: englisch
Anzahl Seiten: 576

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Beschreibungen

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.<br> <br> 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. <br> <br> 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.<br>
Preface<br> <br> A CHEMIST'S SURVEY OF DIFFERENT ANTIBIOTIC CLASSES<br> Introduction<br> Aminoglycosides<br> Beta-Lactams<br> Linear Peptides<br> Cyclic Peptides<br> Thiazolylpeptides<br> Macrolactones<br> Ansamycins-Rifamycins<br> Tetracyclines<br> Oxazolidinones<br> Lincosamides<br> Pleuromutilins<br> Quinolones<br> Aminocoumarins<br> <br> ANTIBACTERIAL DISCOVERY: PROBLEMS AND POSSIBILITIES<br> Introduction<br> Why Is Antibacterial Discovery Difficult? The Problems<br> Target Choice: Essentiality<br> Target Choice: Resistance<br> Cell Entry<br> Screening Strategies<br> Natural Products<br> Computational Chemistry, Virtual Screening, Structure- and Fragment-Based Drug Design (SBDD and FBDD)<br> Conclusions<br> <br> IMPACT OF MICROBIAL NATURAL PRODUCTS ON ANTIBACTERIAL DRUG DISCOVERY<br> Introduction<br> Natural Products for Drug Discovery<br> Microbial Natural Products<br> The Challenge of Finding Novel Antibiotics from New Natural Sources<br> Workflow for Drug Discovery from Microbial Natural Products<br> Antimicrobial Activities: Targets for Screens<br> Natural Products: A Continuing Source for Inspiration<br> Genome Mining in Natural Product Discovery<br> Conclusions<br> <br> ANTIBIOTICS AND RESISTANCE: A FATAL ATTRACTION<br> To Be or Not To Be Resistant: Why and How Antibiotic Resistance Mechanisms Develop and Spread among Bacteria<br> Bacterial Resistance to Antibiotics by Enzymatic Degradation or Modification<br> Antibiotic Target Alteration: The Trick Exists and It Is in the Genetics<br> Efflux Systems<br> The Case Stories of Intrinsic and Acquired Resistances<br> Strategies to Overcome Resistance<br> <br> FITNESS COSTS OF ANTIBIOTIC RESISTANCE<br> Introduction<br> Methods to Estimate Fitness<br> Factors Affecting Fitness<br> Mechanisms and Dynamics Causing Persistence of Chromosomal and Plasmid-Borne Resistance Determinants<br> <br> INHIBITORS OF CELL-WALL SYNTHESIS<br> Introduction<br> MraY Inhibitors<br> Lipid II Targeting Compounds<br> Bactoprenol Phosphate<br> Conclusions<br> <br> INHIBITORS OF BACTERIAL CELL PARTITIONING<br> Introduction<br> Bacterial Cell Division<br> Cell Division Proteins as Therapeutic Targets<br> Status of FtsZ-Targeting Compounds: From Laboratory to Clinic<br> Conclusion<br> <br> THE MEMBRANE AS A NOVEL TARGET SITE FOR ANTIBIOTICS TO KILL PERSISTING BACTERIAL PATHOGENS<br> Introduction<br> The Challenge of Treating Dormant Infections<br> Discovery Strategies to Prevent or Kill Dormant Bacteria<br> Why Targeting the Membrane Could Be a Suitable Strategy<br> Target Essentiality and Selectivity<br> Multiple Modes of Actions<br> Therapeutic Use of Membrane-Damaging Agents against Biofilms<br> New Approaches to Identifying Compounds That Kill Dormant Bacteria<br> Challenges for Biofilm Control with Membrane-Active Agents<br> Potential for Membrane-Damaging Agents in TB Disease<br> Application to Treatment for Clostridium difficile Infection<br> Is Inhibition of Fatty Acid/Phospholipid Biosynthesis Also an Approach?<br> Concluding Remarks<br> <br> BACTERIAL MEMBRANE, A KEY FOR CONTROLLING DRUG INFLUX AND EFFLUX<br> Introduction<br> The Mechanical Barrier<br> Circumventing the Bacterial Membrane Barrier<br> Conclusion<br> <br> INTERFERENCE WITH BACTERIAL CELL-TO-CELL CHEMICAL SIGNALING IN DEVELOPMENT OF NEW ANTI-INFECTIVES<br> Introduction<br> Two-Component Systems (TCSs) as Potential Anti-Infective Targets<br> WalK/WalR and MtrB/MtrA: Case Studies of Essential TCSs as Drug Targets<br> Targeting Nonessential TCS<br> Non-TCSs Targeting Biofilm Formation and Quorum Sensing in Pseudomonas spp.<br> Conclusions<br> <br> RECENT DEVELOPMENTS IN INHIBITORS OF BACTERIAL TYPE IIA TOPOISOMERASES<br> Introduction<br> DNA-Gate Inhibitors<br> ATPase-Domain Inhibitors<br> Simocyclinones, Gyramides, and Other Miscellaneous Inhibitors<br> Conclusions and Perspectives<br> <br> ANTIBIOTICS TARGETING BACTERIAL RNA POLYMERASE<br> Introduction<br> Antibiotics Blocking Nascent RNA Extension<br> Antibiotics Targeting RNAP Active Center<br> Antibiotics Blocking Promoter Complex Formation<br> Inhibitors Hindering Sigma-Core Interactions<br> Inhibitors with Unknown Mechanisms and Binding Sites<br> Conclusions and Perspectives<br> <br> INHIBITORS TARGETING RIBOSWITCHES AND RIBOZYMES<br> Introduction<br> Riboswitches as Antibacterial Drug Targets<br> Ribozymes as Antibacterial Drug Targets<br> Concluding Remarks and Future Perspectives<br> <br> TARGETING RIBONUCLEASE P<br> Introduction<br> Targeting RNase P with Antisense Strategies<br> Aminoglycosides<br> Peptidyltransferase Inhibitors<br> Substrate Masking by Synthetic Inhibitors<br> Peculiar Behavior of Macrolides on Bacterial RNase P<br> Antipsoriatic Compounds<br> Conclusions and Future Perspectives<br> <br> INVOLVEMENT OF RIBOSOME BIOGENESIS IN ANTIBIOTIC FUNCTION, ACQUIRED RESISTANCE, AND FUTURE OPPORTUNITIES IN DRUG DISCOVERY<br> Introduction<br> Ribosome Biogenesis<br> Methyltransferases<br> Methyltransferase Integration into the Ribosome Biogenesis Pathway<br> Ribosome Biogenesis Factors, Virulence, and Vaccine Development<br> <br> AMINOACYL-Trna Synthetase Inhibitors<br> Introduction<br> Enzymatic Mechanism of Action of aaRS<br> aaRS Inhibitors<br> Considerations for the Development of aaRS Inhibitors<br> Conclusions<br> <br> ANTIBIOTICS TARGETING TRANSLATION INITIATION IN PROKARYOTES<br> Introduction<br> Mechanism of Translation Initiation<br> Inhibitors of Folate Metabolism<br> Methionyl-tRNA Formyltransferase<br> Inhibitors of Peptide Deformylase<br> Inhibitors of Translation Initiation Factor IF2<br> ppGpp Analogs as Potential Translation Initiation Inhibitors<br> Translation Initiation Inhibitors Targeting the P-Site<br> <br> INHIBITORS OF BACTERIAL ELONGATION FACTOR EF-Tu<br> Introduction<br> Enacyloxins<br> Kirromycin<br> Pulvomycin<br> GE2270A<br> <br> AMINOGLYCOSIDE ANTIBIOTICS: STRUCTURAL DECODING OF INHIBITORS TARGETING THE RIBOSOMAL DECODING A SITE<br> Introduction<br> Chemical Structures of Aminoglycosides<br> Secondary Structures of the Target A Sites<br> Overview of the Molecular Recognition of Aminoglycosides by the Bacterial A Site<br> Role of Ring I: Specific Recognition of the Binding Pocket<br> Role of Ring II (2-DOS Ring): Locking the A-Site Switch in the "On" State<br> Dual Roles of Extra Rings: Improving the Binding Affinity and Eluding Defense Mechanisms<br> Binding of Semisynthetic Aminoglycosides to the Bacterial A Sites<br> Binding of Aminoglycosides to the Antibiotic-Resistant Bacterial Mutant and Protozoal Cytoplasmic A Sites<br> Binding of Aminoglycosides to the Human A Sites<br> Other Aminoglycosides Targeting the A Site but with Different Modes of Action<br> Aminoglycosides that Do Not Target the A Site<br> Nonaminoglycoside Antibiotic Targeting the A Site<br> Conclusions<br> <br> PEPTIDYLTRANSFERASE INHIBITORS OF THE BACTERIAL RIBOSOME<br> Peptide Bond Formation and Its Inhibition by Antibiotics<br> Puromycin Mimics the CCA-End of tRNAs<br> Chloramphenicols Inhibit A-tRNA Binding in an Amino-Acid-Specific Manner<br> The Oxazolidinones Bind at the A-Site of the PTC<br> Lincosamide Action at the A-Site of the PTC<br> Blasticidin S Mimics the CCA-End of the P-tRNA at the PTC<br> Sparsomycin Prevents A-Site and Stimulates P-Site tRNA Binding<br> Pleuromutilins Overlap A- and P-Sites at the PTC<br> The Synergeistic Action of Streptogramins at the PTC<br> Future Perspectives<br> <br> ANTIBIOTICS INHIBITING THE TRANSLOCATION STEP OF PROTEIN ELONGATION ON THE RIBOSOME<br> Introduction<br> Translocation: Overview<br> Antibiotics Inhibiting Translocation<br> Antibiotics Inhibiting Translocation in Eukaryotes<br> Antibiotics Inhibiting Ribosome Recycling in Bacteria<br> Perspective<br> <br> ANTIBIOTICS AT THE RIBOSOMAL EXIT TUNNEL -<br> SELECTRED STRUCTURAL ASPECTS<br> Introduction<br> The Multifunctional Tunnel<br> A Binding Pocket within the Multifunctional Tunnel<br> Remotely Resistance<br> Resistance Warfare<br> Synergism<br> Pathogen and "Patiens" Models<br> Conclusion and Future Considerations<br> <br> TARGETING HSP70 TO FIGHT CANCER AND BAG BUGS: ONE AND THE SAME BATTLE?<br> A Novel Target: The Bacterial Chaperone HSP70<br> An In vivo Screening for Compounds Targeting DnaK<br> Drugging HSP70<br> Cooperation between the Bacterial Molecular Chaperones DnaK and HtpG<br> Drugging HSP90<br> <br> Index<br>
<p><b>Claudio Gualerzi</b> 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<br />the Alexander von Humboldt foundation for his work on ribosome function and the discovery of novel antibiotics<br /><br /><b>Attilio Fabbretti</b> 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.<br /><b><br />Letizia Brandi</b> 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.</p> <p><b>Cynthia Pon</b> 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</p>
<p>Millions of lives have been saved by antibiotics since the onset of their use in therapy. However, while the golden era of antibiotic discovery is now over the need for effective antibiotics is increased as the antibiotics pipelines have dwindled and life-threatening multi-resistant pathogenic strains have spread.</p> <p>Finding new anti-infective drugs has become a world-wide emergency and a more rational approach to antibiotic development is clearly needed to meet the medical need for next-generation antibiotics.</p> <p>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.</p> <p>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.</p>

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