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Antibiotic Drug Resistance

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Antibiotic Drug Resistance

José-Luis Capelo-Martínez (Editor), Gilberto Igrejas (Editor)

ISBN: 978-1-119-28252-5 September 2019 720 Pages

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Description

This book presents a thorough and authoritative overview of the multifaceted field of antibiotic science – offering guidance to translate research into tools for prevention, diagnosis, and treatment of infectious diseases. 

  • Provides readers with knowledge about the broad field of drug resistance
  • Offers guidance to translate research into tools for prevention, diagnosis, and treatment of infectious diseases
  • Links strategies to analyze microbes to the development of new drugs, socioeconomic impacts to therapeutic strategies, and public policies to antibiotic-resistance-prevention strategies

List of Contributors xix

Preface xxv

About the Editors xxvii

Part I Current Antibiotics and Their Mechanism of Action 1

1 Resistance to Aminoglycosides: Glycomics and the Link to the Human Gut Microbiome 3
Viviana G. Correia, Benedita A. Pinheiro, Ana Luísa Carvalho, and Angelina S. Palma

1.1 Aminoglycosides as Antimicrobial Drugs 3

1.1.1 The Structure of Aminoglycosides 5

1.1.2 Mechanisms of Action 8

1.2 Mechanisms of Resistance 10

1.2.1 Aminoglycoside‐Modifying Enzymes 10

1.2.2 Mutation or Modification of Ribosomal Target Sequences 13

1.2.3 Changes in Uptake and Efflux 14

1.3 Development of New AGAs: The Potential of Glycomics 16

1.3.1 Exploitation of Carbohydrate Chemistry to Study Structure–Activity Relationship of Aminoglycoside Derivatives 17

1.3.2 Aminoglycoside Microarrays to Screen Interactions of Antibiotics with RNAs and Proteins 18

1.4 Influence of the Human Microbiome in Aminoglycoside Resistance 20

1.4.1 The Effect of Antibiotic‐Induced Alterations 21

1.4.2 A Reservoir of Antibiotic Resistance 24

1.4.3 Strategies to Modulate the Human Microbiome 25

1.5 Conclusions and Outlook 26

Acknowledgments 27

References 28

2 Mechanisms of Action and of Resistance to Quinolones 39
José L. Martínez

2.1 Introduction 39

2.2 Mechanism of Action of Quinolones 40

2.3 Mutations in the Genes Encoding the Targets of Quinolones 41

2.4 Multidrug Efflux Pumps and Quinolone Resistance 42

2.5 Transferable Quinolone Resistance 43

2.6 Stenotrophomonas maltophilia and Its Uncommon Mechanisms of Resistance to Quinolones 46

Acknowledgments 47

References 47

3 Beta‐Lactams 57
Luz Balsalobre, Ana Blanco, and Teresa Alarcón

3.1 Introduction 57

3.2 Chemical Structure 58

3.3 Classification and Spectrum of Activity 59

3.3.1 Penicillins 59

3.3.2 Cephalosporins 61

3.3.3 Monobactams 63

3.3.4 Carbapenems 64

3.3.5 Beta‐Lactam Associated with Beta‐Lactamase Inhibitors 64

3.4 Mechanism of Action 66

3.5 Activity of Beta‐Lactams Against Multiresistant Bacteria 68

3.6 Conclusions 70

References 70

4 Glycopeptide Antibiotics: Mechanism of Action and Recent Developments 73
Paramita Sarkar and Jayanta Haldar

4.1 Introduction 73

4.2 Naturally Occurring Glycopeptide Antibiotics 75

4.3 Mechanism of Action of Glycopeptide Antibiotics 76

4.4 Resistance to Glycopeptides 78

4.5 Second‐Generation Glycopeptides 79

4.5.1 Telavancin 79

4.5.2 Dalbavancin 80

4.5.3 Oritavancin 80

4.6 Strategies to Overcome Resistance to Glycopeptides 81

4.6.1 Modifications That Enhance the Binding Affinity to Target Pentapeptide 81

4.6.2 Incorporation of Lipophilicity 85

4.6.3 Incorporation of Lipophilic Cationic Moieties to Impart Membrane Disruption Properties 86

4.6.4 Incorporation of Metal Chelating Moiety to Vancomycin to Impart New Mechanism of Action 88

4.7 Glycopeptides Under Clinical Trials 88

4.8 Glycopeptide Antibiotics: The Challenges 90

References 91

5 Current Macrolide Antibiotics and Their Mechanisms of Action 97
S. Lohsen and D.S. Stephens

5.1 Introduction 97

5.2 Structure of Macrolides 99

5.3 Macrolide Mechanisms of Action 101

5.4 Clinical Use of Macrolides 104

5.5 Next‐Generation Macrolides and Future Use 107

References 109

Part II Mechanism of Antibiotic Resistance 119

6 Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of β‐Lactamases 121
Egorov Alexey, Ulyashova Mariya, and Rubtsova Maya

6.1 Introduction 121

6.2 Structure of the Protein Globule of TEM‐Type β‐Lactamases: Catalytic and Mutated Residues 122

6.2.1 Catalytic Site of β‐Lactamase TEM‐1 124

6.2.2 Mutations Causing Phenotypes of TEM‐Type β‐Lactamases 125

6.3 Effect of the Key Mutations on Activity of TEM‐Type β‐Lactamases 127

6.3.1 Single Key Mutations in TEM‐Type ESBLs (2be) 128

6.3.2 Combinations of Key Mutations in TEM‐Type ESBLs (2be) 130

6.3.3 Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 131

6.3.4 Single Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 131

6.3.5 Combinations of Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 133

6.3.6 Combinations of Key ESBL and IRT Mutations in CMT TEM‐Type β‐Lactamases (2ber) 133

6.4 Effect of Secondary Mutations on the Stability of TEM‐Type β‐Lactamases 134

6.5 Conclusions 135

Abbreviations 136

References 137

7 Acquired Resistance from Gene Transfer 141
Elisabeth Grohmann, Verena Kohler, and Ankita Vaishampayan

7.1 Introduction 141

7.2 Horizonal Gene Transfer: A Brief Overview 143

7.2.1 Transformation 144

7.2.2 Transduction 144

7.2.3 Conjugation 145

7.3 Conjugative Transfer Mechanisms 145

7.3.1 Conjugative Transfer of Plasmids 146

7.3.2 Conjugative Transfer of Integrative Conjugative Elements 148

7.3.3 Conjugative Transfer of Other Integrative Elements 150

7.4 Antibiotic Resistances and Their Transfer 151

7.4.1 Dissemination of Carbapenem Resistance Among Bacterial Pathogens 151

7.4.2 Dissemination of Cephalosporin Resistance Among Bacterial Pathogens 153

7.4.3 Dissemination of Methicillin Resistance Among Bacterial Pathogens 153

7.4.4 Dissemination of Vancomycin Resistance Among Bacterial Pathogens 154

7.4.5 Dissemination of Fluoroquinolone Resistance Among Bacterial Pathogens 154

7.4.6 Dissemination of Penicillin and Ampicillin Resistance Among Bacterial Pathogens 155

7.5 Nanotubes Involved in Acquisition of Antibiotic Resistances 155

7.6 Conclusions and Outlook 156

Abbreviations 156

References 157

8 Antimicrobial Efflux Pumps 167
Manuel F. Varela

8.1 Bacterial Antimicrobial Efflux Pumps 167

8.1.1 Active Drug Efflux Systems 167

8.1.2 Secondary Active Drug Transporters 169

References 173

9 Bacterial Persistence in Biofilms and Antibiotics: Mechanisms Involved 181
Anne Jolivet‐Gougeon and Martine Bonnaure‐Mallet

9.1 Introduction 181

9.2 Reasons for Failure of Antibiotics in Biofilms 182

9.2.1 Failure of Antibiotics to Penetrate Biofilm: Active Antibiotics on the Biofilm 182

9.2.2 Outer Membrane Vesicles (OMVs) 183

9.2.3 Horizontal Transfer of Encoding β‐Lactamase Genes 184

9.2.4 Influence of Subinhibitory Concentrations of Antibiotics on Biofilm 184

9.2.5 Small Colony Variants (SCVs), Persistence (Persisters), and Toxin–Antitoxin (TA) Systems 186

9.2.6 Quorum Sensing: Bacterial Metabolites 191

9.2.7 Extracellular DNA 191

9.2.8 Nutrient Limitation 192

9.2.9 SOS Inducers (Antibiotics and Others) 192

9.2.10 Hypermutator Phenotype 192

9.2.11 Multidrug Efflux Pumps 193

9.3 Usual and Innovative Means to Overcome Biofilm Resistance in Biofilms 193

9.3.1 Antibiotics (Bacteriocins) Natural and Synthetic Molecules: Phages 194

9.3.2 Efflux Pump Inhibitors 195

9.3.3 Anti‐Persisters: Quorum‐Sensing Inhibitors 195

9.3.4 Enzymes 196

9.3.5 Electrical Methods 196

9.3.6 Photodynamic Therapy 196

9.4 Conclusion 197

Acknowledgments 197

Conflict of Interest 197

References 197

Part III Socio-Economical Perspectives and Impact of AR 211

10 Sources of Antibiotic Resistance: Zoonotic, Human, Environment 213
Ivone Vaz‐Moreira, Catarina Ferreira, Olga C. Nunes, and Célia M. Manaia

10.1 The Antibiotic Era 213

10.2 Intrinsic and Acquired Antibiotic Resistance 214

10.3 The Natural Antibiotic Resistome 215

10.4 The Contaminant Resistome 215

10.5 Evolution of Antibiotics Usage 216

10.6 Antibiotic Resistance Evolution 219

10.7 Stressors for Antibiotic Resistance 219

10.8 Paths of Antibiotic Resistance Dissemination 221

10.9 Antibiotic Resistance in Humans and Animals 224

10.10 Final Considerations 227

References 228

11 Antibiotic Resistance: Immunity‐Acquired Resistance: Evolution of Antimicrobial Resistance Among Extended‐Spectrum β‐Lactamases and Carbapenemases in Klebsiella pneumonia and Escherichia coli 239
Isabel Carvalho, Nuno Silva, João Carrola, Vanessa Silva, Carol Currie, Gilberto Igrejas, and Patrícia Poeta

11.1 Overview of Antibiotic Resistance as a Worldwide Health Problem 239

11.2 Objectives 241

11.3 Causes of Antimicrobial Resistance 242

11.4 Enterobacteriaceae: General Characterization 243

11.4.1 Escherichia coli 243

11.4.2 Klebsiella pneumoniae 244

11.5 Current Antibiotic Resistance Threats 245

11.5.1 Carbapenem‐Resistant Enterobacteriaceae 245

11.5.2 Extended‐Spectrum β‐Lactamase 247

11.6 Consequences and Future Strategies to Brace the Antibiotic Backbone 250

11.7 Concluding Remarks and Future Perspectives 251

Acknowledgments 252

References 252

12 Extended‐Spectrum‐β‐Lactamase and Carbapenemase‐Producing Enterobacteriaceae in Food‐Producing Animals in Europe: An Impact on Public Health? 261
Nuno Silva, Isabel Carvalho, Carol Currie, Margarida Sousa, Gilberto Igrejas, and Patrícia Poeta

12.1 Extended‐Spectrum β‐Lactamase 261

12.1.1 ESBL‐Producing Enterobacteriaceae in Food Animals 262

12.2 Carbapenemases 265

12.3 Concluding Remarks 267

References 268

Part IV Therapeutic Strategy for Overcoming AR 275

13 AR Mechanism‐Based Drug Design 277
Mire Zloh

13.1 Introduction 277

13.2 Drug Design Principles 279

13.3 Identification of Novel Targets and Novel Mechanisms of Action 282

13.4 Efflux Pump Inhibitors 286

13.5 Design of Inhibitors of Drug‐Modifying Enzymes 294

13.6 Antimicrobial Peptides 297

13.7 Other Approaches to Overcome Bacterial Resistance 299

13.8 Conclusion 300

References 300

14 Antibiotics from Natural Sources 311
David J. Newman

14.1 Introduction 311

14.1.1 The Origin of Microbial Resistance Gene Products 311

14.2 Organization of the Following Sections 312

14.3 Peptidic Antibiotics (Both Cyclic and Acyclic) 312

14.3.1 Tyrocidines, Gramacidins, and Derivatives 312

14.3.2 Streptogramins and Derivatives: Cyclic Peptides 313

14.3.3 Arylomycins (Lipopeptide and Modification, Preclinical) 313

14.3.4 Daptomycin (Cyclic Depsilipopeptide) 314

14.3.5 Colistins (Cyclic Peptides with a Lipid Tail) 315

14.3.6 Glycopeptides 317

14.3.7 Host Defense Peptides 319

14.4 β‐Lactams: Development, Activities, and Chemistry 321

14.4.1 Combinations with β‐Lactamase Inhibitors 322

14.5 Aminoglycosides 323

14.5.1 Streptomycin 323

14.5.2 Plazomicin 323

14.6 Early Tetracyclines: Aureomycin and Terramycin 324

14.6.1 Semisynthetic Tetracyclines from 2005 324

14.7 Erythromycin Macrolides 326

14.7.1 Recent Semisynthetic Macrolides 326

14.8 Current Methods of “Discovering Novel Antibiotics” 328

14.8.1 Introduction 328

14.8.2 Initial Rate‐Limiting Step (Irrespective of Methods) 328

14.8.3 Genomic Analyses of Whole Microbes 329

14.8.4 Isolated Genomics 329

14.8.5 New Sources (and Old Ones?) for Investigation 331

14.8.6 “Baiting” for Microbes 331

14.8.7 Use of Elicitors 333

14.9 Conclusions 333

14.9.1 Funding? 334

14.9.2 The “Take‐Home Lesson” 334

References 334

15 Bacteriophage Proteins as Antimicrobials to Combat Antibiotic Resistance 343
Hugo Oliveira, Luís D. R. Melo, and Sílvio B. Santos

15.1 Introduction 343

15.2 Polysaccharide Depolymerases 346

15.2.1 Depolymerase Structure 348

15.2.2 Depolymerase Classification 349

15.2.3 Depolymerase Activity Assessment 350

15.2.4 Depolymerases as Antimicrobials 351

15.2.5 Remarks on Depolymerases 355

15.3 Peptidoglycan‐Degrading Enzymes 356

15.3.1 Virion‐Associated Lysins (VALs) 358

15.3.2 Gram‐Positive Targeting Endolysins 365

15.3.3 Gram‐Negative Targeting Endolysins 374

15.4 Holins 388

15.4.1 Holin Structure 388

15.4.2 Holins as Antimicrobials 389

15.4.3 Remarks on Holins 390

15.5 Final Considerations 390

References 392

16 Antibiotic Modification Addressing Resistance 407
Haotian Bai and Shu Wang

16.1 Chemical Synthesis of New Antibiotics 407

16.2 Antibiotic Modification with Targeted Groups 413

16.3 Antibiotic Modification with Photo‐Switching Units 417

16.4 Antibiotic Modification by Supramolecular Chemistry 420

16.5 Antibiotic Modification by Complexed with Other Materials 423

16.6 Conclusion 425

References 425

17 Sensitizing Agents to Restore Antibiotic Resistance 429
Anton Gadelii, Karl‐Omar Hassan, and Anders P. Hakansson

17.1 Introduction 429

17.2 Sensitizing Strategies Directly Targeting Resistance Mechanisms 430

17.2.1 Inhibition of β‐Lactamases 430

17.2.2 Drug Efflux Pump Inhibitors (EPIs) 433

17.3 Sensitizing Strategies Circumventing Resistance Mechanisms 435

17.3.1 Manipulating Bacterial Homeostasis 435

17.3.2 Cell Wall/Membrane Proteins 437

17.3.3 Biofilms and Quorum Sensing 438

17.3.4 Persister Cells 440

17.3.5 Targeting Nonessential Genes/Proteins 441

17.3.6 Bacteriophages 441

17.4 Using and Strengthening the Human Immune System Against Resistant Bacteria 441

17.4.1 Strengthening Host Immune System Function 441

17.4.2 Antimicrobial Peptides (AMPs) 443

17.5 Conclusion 443

References 444

18 Repurposing Antibiotics to Treat Resistant Gram‐Negative Pathogens 453
Frank Schweizer

18.1 Introduction 453

18.2 Anti‐Virulence Strategy 454

18.3 Antibiotic Combination Strategy 454

18.4 Antibiotic–Antibiotic Combination Approach 455

18.5 Antibiotic–Adjuvant Combination Approach 456

18.6 β‐Lactam and β‐Lactamase Inhibitor Combination 456

18.7 Imipenem–Cilastatin/Relebactam Triple Combination 457

18.8 Aspergillomarasmine A 458

18.9 Intrinsic Resistance Challenges and Strategies to Overcome Them 458

18.10 Repurposing of Hydrophobic Antibiotics with High Molecular Weight by Enhancing Outer Membrane Permeability Using Polybasic Adjuvants 461

18.11 Repurposing of Hydrophobic Antibiotics with Large Molecular Weight and Other Antibacterials as Antipseudomonal Agents Using Polybasic Adjuvants 464

18.12 Repurposing of Antibiotics as Potent Agents Against MDR GNB 467

18.13 Outlook and Conclusions 468

References 468

19 Nontraditional Medicines for Treatment of Antibiotic Resistance 477
Ana Paula Guedes Frazzon, Michele Bertoni Mann, and Jeverson Frazzon

19.1 Introduction 477

19.2 Antibodies 478

19.2.1 Raxibacumab Versus Bacillus anthracis 478

19.2.2 Bezlotoxumab Versus Clostridium difficile 479

19.2.3 Panobacumab Versus Pseudomonas aeruginosa 479

19.2.4 LC10 Versus Staphylococcus aureus 480

19.3 Immunomodulators 481

19.3.1 Antibodies plus Polymyxins 481

19.3.2 Antibodies plus Vitamin D 482

19.3.3 Antibodies plus Clavanin 482

19.3.4 Antibodies plus Reltecimod 483

19.4 Potentiators of Antibiotic Activity 483

19.4.1 Antibiotic–Antibiotic Combinations 484

19.4.2 Pairing of Antibiotic with Nonantibiotic 485

19.5 Bacteriophages 488

19.5.1 Life Cycles of Bacteriophages 488

19.5.2 Bacteriophage Therapy 489

19.5.3 Phage Enzymes 490

19.5.4 Concerns About the Application of Phage to Treat Bacteria 491

19.6 Therapy with Essential Oils 491

19.7 Microbiota‐Based Therapy 495

19.7.1 Microbiota Modulation 495

19.7.1.1 Probiotics 496

19.7.1.2 Prebiotics 496

19.7.2 Stool Microbiota Transplant 496

Further Reading 497

20 Therapeutic Options for Treatment of Infections by Pathogenic Biofilms 503
Bruna de Oliveira Costa, Osmar Nascimento Silva, and Octávio Luiz Franco

20.1 Introduction 503

20.2 Antibiotic Therapy for the Treatment of Pathogenic Biofilms 504

20.2.1 Monotherapy 504

20.2.2 Antibiotic Combination Therapy 505

20.3 New Findings for the Treatment of Pathogenic Biofilms 507

20.3.1 AMPs Applied to Treatment Pathogenic Biofilms 507

20.3.2 Bacteriophage Therapy Anti‐Biofilm 514

20.3.3 Nanotechnology Applied to the Treatment of Pathogenic Biofilms 517

20.4 Conclusion and Future Directions 519

References 520

Part V Strategies to Prevent the Spread of AR 533

21 Rapid Analytical Methods to Identify Antibiotic‐Resistant Bacteria 535
John B. Sutherland, Fatemeh Rafii, Jackson O. Lay, Jr., and Anna J. Williams

21.1 Introduction 535

21.2 Standard Methods for Antibiotic Sensitivity Testing 536

21.3 Rapid Cultural Methods 537

21.4 Rapid Serological Methods 540

21.5 Rapid Molecular (Genetic) Methods 540

21.6 Mass Spectrometric Methods 545

21.7 Flow Cytometric Methods 549

21.8 Conclusions 550

Acknowledgments 553

References 553

22 Effective Methods for Disinfection and Sterilization 567
Lucía Fernández, Diana Gutiérrez, Beatriz Martínez, Ana Rodríguez, and Pilar García

22.1 Introduction 567

22.2 Disinfection and Sterilization: Methods and Factors Involved in Their Efficacy 569

22.2.1 Methods of Sterilization and Disinfection 570

22.2.2 Factors Influencing Disinfection and Sterilization Efficacy 570

22.3 Resistance to Disinfectants 571

22.3.1 Molecular Mechanisms of Biocide Resistance 571

22.3.2 Biofilms 572

22.3.3 Cross‐Resistance Between Antibiotics and Disinfectants 574

22.4 New Technologies as Alternatives to Classical Disinfectants 575

22.4.1 Chemical and Physical Disinfectants 575

22.4.2 Antimicrobial Surfaces 578

22.4.3 Biological Disinfectants 578

22.5 Current Legislation 579

22.6 Conclusions 581

References 582

23 Strategies to Prevent the Spread of Antibiotic Resistance: Understanding the Role of Antibiotics in Nature and Their Rational Use 589
Rustam Aminov

23.1 Introduction 589

23.2 Agriculture as the Largest Consumer of Antimicrobials 590

23.3 Antimicrobials and Antimicrobial Resistance 591

23.4 First‐Generation Tetracyclines: Discovery and Usage 592

23.5 Tetracycline Resistance Mechanisms 593

23.6 Phylogeny of Tetracycline Resistance Genes 593

23.7 Second‐Generation Tetracyclines 595

23.8 Third‐Generation Tetracyclines 595

23.9 Resistance to Third‐Generation Tetracyclines 596

23.10 Other Potential Resistance Mechanisms Toward Third‐Generation Tetracyclines 597

23.11 Evolutionary Aspect of tet(X) 598

23.12 Ecological Aspects of tet(X) 599

23.13 Antibiotics and Antibiotic Resistance as Integral Parts of Microbial Diversity 602

23.14 The Role of Antibiotics in Natural Ecosystems 604

23.15 Low‐Dose Antibiotics: Phenotypic Effects 605

23.16 Low‐Dose Antibiotics: Genetic Effects 606

23.17 Regulation of Antibiotic Synthesis in Antibiotic Producers 608

23.18 Convergent Evolution of Antibiotics as Signaling Molecules 610

23.19 Carbapenems: Convergent Evolution and Regulation in Different Bacteria 611

23.20 Antibiotics and Antibiotic Resistance: Environmental and Anthropogenic Contexts 614

23.21 Conclusions 615

Conflict of Interest 616

References 616

Part VI Public Policy 637

24 Strategies to Reduce or Eliminate Resistant Pathogens in the Environment 639
Johan Bengtsson‐Palme and Stefanie Heß

24.1 Introduction 639

24.2 Sources of Resistant Bacteria in the Environment 640

24.3 Sewage and Wastewater 641

24.3.1 Sewage Treatment Plants 641

24.3.2 Non‐Treated Sewage 643

24.3.3 Industrial Wastewater Effluents 643

24.3.4 Environmental Antibiotic Resistance is a Poverty Problem 644

24.4 Agriculture 646

24.4.1 Intensive, Large‐Scale Animal Husbandry 646

24.4.2 Manure Application 647

24.4.3 Agriculture in Developing Countries 647

24.4.4 Aquaculture 648

24.5 De Novo Resistance Selection 649

24.6 Relevant Risk Scenarios 649

24.7 Management Options 653

24.7.1 Possible Interventions on the Level of Releases of Resistant Bacteria 653

24.7.2 Restricting Transmission of Resistant Bacteria from the Environment 657

24.7.3 Better Agriculture Practices to Sustain the Lifespans of Antibiotics 658

24.7.4 Limiting Selection for Resistance in the Environment 659

24.8 Final Remarks 661

Acknowledgments 662

Conflict of Interest 662

References 662

Index 675