Antibiotics: Targets, Mechanisms and Resistance

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.

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

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