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
Table of Contents
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
