Main 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.

Contents:

Preface XVII List of Contributors XIX 1 A Chemist's Survey of Different Antibiotic Classes 1 Sonia Ilaria Maffioli 1.1 Introduction 1 1.2 Aminoglycosides 1 1.3 -Lactams 3 1.4 Linear Peptides 4 1.5 Cyclic Peptides 8 1.6 Thiazolylpeptides 11 1.7 Macrolactones 13 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 2 Antibacterial Discovery: Problems and Possibilities 23 Lynn L. Silver 2.1 Introduction 23 2.2 Why Is Antibacterial Discovery Difficult? The Problems 24 2.3 Target Choice: Essentiality 24 2.4 Target Choice: Resistance 26 2.5 Cell Entry 31 2.6 Screening Strategies 32 2.7 Natural Products 40 2.8 Computational Chemistry, Virtual Screening, Structure- and Fragment-Based Drug Design (SBDD and FBDD) 42 2.9 Conclusions 45 3 Impact of Microbial Natural Products on Antibacterial Drug Discovery 53 Gabriella Molinari 3.1 Introduction 53 3.2 Natural Products for Drug Discovery 54 3.3 Microbial Natural Products 56 3.4 The Challenge of Finding Novel Antibiotics from New Natural Sources 59 3.5 Workflow for Drug Discovery from Microbial Natural Products 60 3.6 Antimicrobial Activities: Targets for Screens 63 3.7 Natural Products: A Continuing Source for Inspiration 65 3.8 Genome Mining in Natural Product Discovery 66 3.9 Conclusions 67 4 Antibiotics and Resistance: A Fatal Attraction 73 Giuseppe Gallo and Anna Maria Puglia 4.1 To Be or Not to Be Resistant: Why and How Antibiotic Resistance Mechanisms Develop and Spread among Bacteria 73 4.1.1 Horizontal and Vertical Transmission of Resistance Genes 74 4.2 Bacterial Resistance to Antibiotics by Enzymatic Degradation or Modification 79 4.3 Antibiotic Target Alteration: The Trick Exists and It Is in the Genetics 86 4.4 Efflux Systems 92 4.5 The Case Stories of Intrinsic and Acquired Resistances 98 4.6 Strategies to Overcome Resistance 100 5 Fitness Costs of Antibiotic Resistance 109 Pietro Alifano 5.1 Introduction 109 5.2 Methods to Estimate Fitness 110 5.3 Factors Affecting Fitness 112 5.4 Mechanisms and Dynamics Causing Persistence of Chromosomal and Plasmid-Borne Resistance Determinants 121 6 Inhibitors of Cell-Wall Synthesis 133 Stefano Donadio and Margherita Sosio 6.1 Introduction 133 6.2 MraY Inhibitors 134 6.3 Lipid II Targeting Compounds 137 6.4 Bactoprenol Phosphate 145 6.5 Conclusions 146 7 Inhibitors of Bacterial Cell Partitioning 151 Bhavya Jindal, Anusri Bhattacharya, and Dulal Panda 7.1 Introduction 151 7.2 Bacterial Cell Division 152 7.3 Cell Division Proteins as Therapeutic Targets 158 7.4 Status of FtsZ-Targeting Compounds: From Laboratory to Clinic 172 7.5 Conclusion 173 8 The Membrane as a Novel Target Site for Antibiotics to Kill Persisting Bacterial Pathogens 183 Xiaoqian Wu and Julian G. Hurdle 8.1 Introduction 183 8.2 The Challenge of Treating Dormant Infections 184 8.3 Discovery Strategies to Prevent or Kill Dormant Bacteria 185 8.4 Why Targeting the Membrane Could Be a Suitable Strategy 186 8.5 Target Essentiality and Selectivity 186 8.6 Multiple Modes of Actions 188 8.7 Therapeutic Use of Membrane-Damaging Agents against Biofilms 190 8.8 New Approaches to Identifying Compounds That Kill Dormant Bacteria 196 8.9 Challenges for Biofilm Control with Membrane-Active Agents 196 8.10 Potential for Membrane-Damaging Agents in TB Disease 200 8.11 Application to Treatment of Clostridium difficile Infection 202 8.12 Is Inhibition of Fatty Acid/Phospholipid Biosynthesis Also an Approach? 203 8.13 Concluding Remarks 204 9 Bacterial Membrane, a Key for Controlling Drug Influx and Efflux 217 Eric Valade, Anne Davin-Regli, Jean-Michel Bolla, and Jean-Marie Pag'es 9.1 Introduction 217 9.2 The Mechanical Barrier 219 9.3 Circumventing the Bacterial Membrane Barrier 224 9.4 Conclusion 229 10 Interference with Bacterial Cell-to-Cell Chemical Signaling in Development of New Anti-Infectives 241 Jacqueline W. Njoroge and Vanessa Sperandio 10.1 Introduction 241 10.2 Two-Component Systems (TCSs) as Potential Anti-Infective Targets 242 10.3 WalK/WalR and MtrB/MtrA: Case Studies of Essential TCSs as Drug Targets 243 10.4 Targeting Nonessential TCS 246 10.5 Non-TCSs Targeting Biofilm Formation and Quorum Sensing in Pseudomonas spp. 250 10.6 Conclusions 253 11 Recent Developments in Inhibitors of Bacterial Type IIA Topoisomerases 263 Pan F. Chan, Jianzhong Huang, Benjamin D. Bax, andMichael N. Gwynn 11.1 Introduction 263 11.2 DNA-Gate Inhibitors 267 11.3 ATPase-Domain Inhibitors 276 11.4 Simocyclinones, Gyramides, and Other Miscellaneous Inhibitors 284 11.5 Conclusions and Perspectives 287 12 Antibiotics Targeting Bacterial RNA Polymerase 299 Konstantin Brodolin 12.1 Introduction 299 12.2 Antibiotics Blocking Nascent RNA Extension 304 12.3 Antibiotics Targeting RNAP Active Center 307 12.4 Antibiotics Blocking Promoter Complex Formation 310 12.5 Inhibitors Hindering Core Interactions 313 12.6 Inhibitors with Unknown Mechanisms and Binding Sites 314 12.7 Conclusions and Perspectives 315 13 Inhibitors Targeting Riboswitches and Ribozymes 323 Isabella Moll, Attilio Fabbretti, Letizia Brandi, and Claudio O. Gualerzi 13.1 Introduction 323 13.2 Riboswitches as Antibacterial Drug Targets 323 13.3 Ribozymes as Antibacterial Drug Targets 340 13.4 Concluding Remarks and Future Perspectives 344 14 Targeting Ribonuclease P 355 Chrisavgi Toumpeki, Vassiliki Stamatopoulou, Maria Bikou, Katerina Grafanaki, Sophia Kallia-Raftopoulou, Dionysios Papaioannou, Constantinos Stathopoulos, and Denis Drainas 14.1 Introduction 355 14.2 Targeting RNase P with Antisense Strategies 357 14.3 Aminoglycosides 359 14.4 Peptidyltransferase Inhibitors 361 14.5 Substrate Masking by Synthetic Inhibitors 363 14.6 Peculiar Behavior of Macrolides on Bacterial RNase P 363 14.7 Antipsoriatic Compounds 364 14.8 Conclusions and Future Perspectives 366 15 Involvement of Ribosome Biogenesis in Antibiotic Function, Acquired Resistance, and Future Opportunities in Drug Discovery 371 Gloria M. Culver and Jason P. Rife 15.1 Introduction 371 15.2 Ribosome Biogenesis 372 15.3 Antibiotics and Ribosome Biogenesis 373 15.4 Methyltransferases 375 15.5 Methyltransferase Integration into the Ribosome Biogenesis Pathway 380 15.6 Ribosome Biogenesis Factors, Virulence, and Vaccine Development 381 16 Aminoacyl-tRNA Synthetase Inhibitors 387 Urs A. Ochsner and Thale C. Jarvis 16.1 Introduction 387 16.2 Enzymatic Mechanism of Action of aaRS 388 16.3 aaRS Inhibitors 393 16.4 Considerations for the Development of aaRS Inhibitors 403 16.5 Conclusions 405 17 Antibiotics Targeting Translation Initiation in Prokaryotes 411 Cynthia L. Pon, Attilio Fabbretti, Letizia Brandi, and Claudio O. Gualerzi 17.1 Introduction 411 17.2 Mechanism of Translation Initiation 411 17.3 Inhibitors of Folate Metabolism 414 17.4 Methionyl-tRNA Formyltransferase 417 17.5 Inhibitors of Peptide Deformylase 417 17.6 Inhibitors of Translation Initiation Factor IF2 418 17.7 ppGpp Analogs as Potential Translation Initiation Inhibitors 422 17.8 Translation Initiation Inhibitors Targeting the P-Site 423 18 Inhibitors of Bacterial Elongation Factor EF-Tu 437 Attilio Fabbretti, Anna Maria Giuliodori, and Letizia Brandi 18.1 Introduction 437 18.2 Enacyloxins 438 18.3 Kirromycin 444 18.4 Pulvomycin 446 18.5 GE2270A 448 19 Aminoglycoside Antibiotics: Structural Decoding of Inhibitors Targeting the Ribosomal Decoding A Site 453 Jiro Kondo and Eric Westhof 19.1 Introduction 453 19.2 Chemical Structures of Aminoglycosides 455 19.3 Secondary Structures of the Target A Sites 455 19.4 Overview of the Molecular Recognition of Aminoglycosides by the Bacterial A Site 458 19.5 Role of Ring I: Specific Recognition of the Binding Pocket 459 19.6 Role of Ring II (2-DOS Ring): Locking the A-Site Switch in the "On" State 459 19.7 Dual Roles of Extra Rings: Improving the Binding Affinity and Eluding Defense Mechanisms 461 19.8 Binding of Semisynthetic Aminoglycosides to the Bacterial A Sites 463 19.9 Binding of Aminoglycosides to the Antibiotic-Resistant Bacterial Mutan and Protozoal Cytoplasmic A Sites 464 19.10 Binding of Aminoglycosides to the Human A Sites 464 19.11 Other Aminoglycosides Targeting the A Site but with Different Modes of Action 465 19.12 Aminoglycosides that Do Not Target the A Site 465 19.13 Nonaminoglycoside Antibiotic Targeting the A Site 466 19.14 Conclusions 466 20 Peptidyltransferase Inhibitors of the Bacterial Ribosome 471 Daniel Wilson 20.1 Peptide Bond Formation and Its Inhibition by Antibiotics 471 20.2 Puromycin Mimics the CCA-End of tRNAs 472 20.3 Chloramphenicols Inhibit A-tRNA Binding in an Amino-Acid-Specific Manner 475 20.4 The Oxazolidinones Bind at the A-Site of the PTC 476 20.5 Lincosamide Action at the A-Site of the PTC 478 20.6 Blasticidin S Mimics the CCA-End of the P-tRNA at the PTC 478 20.7 Sparsomycin Prevents A-Site and Stimulates P-Site tRNA Binding 480 20.8 Pleuromutilins Overlap A- and P-Sites at the PTC 481 20.9 The Synergistic Action of Streptogramins at the PTC 483 20.10 Future Perspectives 484 21 Antibiotics Inhibiting the Translocation Step of Protein Elongation on the Ribosome 491 Frank Peske and Wolfgang Wintermeyer 21.1 Introduction 491 21.2 Translocation: Overview 491 21.3 Antibiotics Inhibiting Translocation 494 21.4 Antibiotics Inhibiting Translocation in Eukaryotes 500 21.5 Antibiotics Inhibiting Ribosome Recycling in Bacteria 501 21.6 Perspective 503 22 Antibiotics at the Ribosomal Exit Tunnel Selected Structural Aspects 509 Ella Zimmerman, Anat Bashan, and Ada Yonath 22.1 Introduction 509 22.2 The Multifunctional Tunnel 510 22.3 A Binding Pocket within the Multifunctional Tunnel 512 22.4 Remotely Resistance 513 22.5 Resistance Warfare 514 22.6 Synergism 515 22.7 Pathogen and Patients Models 517 22.8 Conclusion and Future Considerations 519 23 Targeting HSP70 to Fight Cancer and Bad Bugs: One and the Same Battle? 525 Jean-Herv'e Alix 23.1 A Novel Target: The Bacterial Chaperone HSP70 525 23.2 An In vivo Screening for Compounds Targeting DnaK 528 23.3 Drugging HSP70 528 23.4 Cooperation between the Bacterial Molecular Chaperones DnaK and HtpG 530 23.5 Drugging HSP90 531 References 532 Index 539