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Antibiotics: Targets, Mechanisms and Resistance

Antibiotics: Targets, Mechanisms and Resistance

Claudio O. Gualerzi (Editor), Letizia Brandi (Editor), Attilio Fabbretti (Editor), Cynthia L. Pon (Editor)

ISBN: 978-3-527-65968-5

Oct 2013

576 pages

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.

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 β-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 σ–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