JOSÉ-LUIS CAPELO-MARTÍNEZ PHD, is Associate Professor in the Department of Chemistry of the Faculty of Science and Technology of the NOVA University of Lisbon. GILBERTO IGREJAS PHD, is an Associate Professor with habilitation in the Department of Genetics and Biotechnology at the University of Trás-os-Montes and Alto Douro in Portugal.

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• List of Contributors xixPreface xxvAbout the Editors xxviiPart I Current Antibiotics and Their Mechanism of Action 11 Resistance to Aminoglycosides: Glycomics and the Link to the Human Gut Microbiome 3Viviana G. Correia, Benedita A. Pinheiro, Ana Luísa Carvalho, and Angelina S. Palma1.1 Aminoglycosides as Antimicrobial Drugs 31.1.1 The Structure of Aminoglycosides 51.1.2 Mechanisms of Action 81.2 Mechanisms of Resistance 101.2.1 Aminoglycoside‐Modifying Enzymes 101.2.2 Mutation or Modification of Ribosomal Target Sequences 131.2.3 Changes in Uptake and Efflux 141.3 Development of New AGAs: The Potential of Glycomics 161.3.1 Exploitation of Carbohydrate Chemistry to Study Structure–Activity Relationship of Aminoglycoside Derivatives 171.3.2 Aminoglycoside Microarrays to Screen Interactions of Antibiotics with RNAs and Proteins 181.4 Influence of the Human Microbiome in Aminoglycoside Resistance 201.4.1 The Effect of Antibiotic‐Induced Alterations 211.4.2 A Reservoir of Antibiotic Resistance 241.4.3 Strategies to Modulate the Human Microbiome 251.5 Conclusions and Outlook 26Acknowledgments 27References 282 Mechanisms of Action and of Resistance to Quinolones 39José L. Martínez2.1 Introduction 392.2 Mechanism of Action of Quinolones 402.3 Mutations in the Genes Encoding the Targets of Quinolones 412.4 Multidrug Efflux Pumps and Quinolone Resistance 422.5 Transferable Quinolone Resistance 432.6 Stenotrophomonas maltophilia and Its Uncommon Mechanisms of Resistance to Quinolones 46Acknowledgments 47References 473 Beta‐Lactams 57Luz Balsalobre, Ana Blanco, and Teresa Alarcón3.1 Introduction 573.2 Chemical Structure 583.3 Classification and Spectrum of Activity 593.3.1 Penicillins 593.3.2 Cephalosporins 613.3.3 Monobactams 633.3.4 Carbapenems 643.3.5 Beta‐Lactam Associated with Beta‐Lactamase Inhibitors 643.4 Mechanism of Action 663.5 Activity of Beta‐Lactams Against Multiresistant Bacteria 683.6 Conclusions 70References 704 Glycopeptide Antibiotics: Mechanism of Action and Recent Developments 73Paramita Sarkar and Jayanta Haldar4.1 Introduction 734.2 Naturally Occurring Glycopeptide Antibiotics 754.3 Mechanism of Action of Glycopeptide Antibiotics 764.4 Resistance to Glycopeptides 784.5 Second‐Generation Glycopeptides 794.5.1 Telavancin 794.5.2 Dalbavancin 804.5.3 Oritavancin 804.6 Strategies to Overcome Resistance to Glycopeptides 814.6.1 Modifications That Enhance the Binding Affinity to Target Pentapeptide 814.6.2 Incorporation of Lipophilicity 854.6.3 Incorporation of Lipophilic Cationic Moieties to Impart Membrane Disruption Properties 864.6.4 Incorporation of Metal Chelating Moiety to Vancomycin to Impart New Mechanism of Action 884.7 Glycopeptides Under Clinical Trials 884.8 Glycopeptide Antibiotics: The Challenges 90References 915 Current Macrolide Antibiotics and Their Mechanisms of Action 97S. Lohsen and D.S. Stephens5.1 Introduction 975.2 Structure of Macrolides 995.3 Macrolide Mechanisms of Action 1015.4 Clinical Use of Macrolides 1045.5 Next‐Generation Macrolides and Future Use 107References 109Part II Mechanism of Antibiotic Resistance 1196 Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of β‐Lactamases 121Egorov Alexey, Ulyashova Mariya, and Rubtsova Maya6.1 Introduction 1216.2 Structure of the Protein Globule of TEM‐Type β‐Lactamases: Catalytic and Mutated Residues 1226.2.1 Catalytic Site of β‐Lactamase TEM‐1 1246.2.2 Mutations Causing Phenotypes of TEM‐Type β‐Lactamases 1256.3 Effect of the Key Mutations on Activity of TEM‐Type β‐Lactamases 1276.3.1 Single Key Mutations in TEM‐Type ESBLs (2be) 1286.3.2 Combinations of Key Mutations in TEM‐Type ESBLs (2be) 1306.3.3 Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 1316.3.4 Single Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 1316.3.5 Combinations of Key Mutations in IRT TEM‐Type β‐Lactamases (2br) 1336.3.6 Combinations of Key ESBL and IRT Mutations in CMT TEM‐Type β‐Lactamases (2ber) 1336.4 Effect of Secondary Mutations on the Stability of TEM‐Type β‐Lactamases 1346.5 Conclusions 135Abbreviations 136References 1377 Acquired Resistance from Gene Transfer 141Elisabeth Grohmann, Verena Kohler, and Ankita Vaishampayan7.1 Introduction 1417.2 Horizonal Gene Transfer: A Brief Overview 1437.2.1 Transformation 1447.2.2 Transduction 1447.2.3 Conjugation 1457.3 Conjugative Transfer Mechanisms 1457.3.1 Conjugative Transfer of Plasmids 1467.3.2 Conjugative Transfer of Integrative Conjugative Elements 1487.3.3 Conjugative Transfer of Other Integrative Elements 1507.4 Antibiotic Resistances and Their Transfer 1517.4.1 Dissemination of Carbapenem Resistance Among Bacterial Pathogens 1517.4.2 Dissemination of Cephalosporin Resistance Among Bacterial Pathogens 1537.4.3 Dissemination of Methicillin Resistance Among Bacterial Pathogens 1537.4.4 Dissemination of Vancomycin Resistance Among Bacterial Pathogens 1547.4.5 Dissemination of Fluoroquinolone Resistance Among Bacterial Pathogens 1547.4.6 Dissemination of Penicillin and Ampicillin Resistance Among Bacterial Pathogens 1557.5 Nanotubes Involved in Acquisition of Antibiotic Resistances 1557.6 Conclusions and Outlook 156Abbreviations 156References 1578 Antimicrobial Efflux Pumps 167Manuel F. Varela8.1 Bacterial Antimicrobial Efflux Pumps 1678.1.1 Active Drug Efflux Systems 1678.1.2 Secondary Active Drug Transporters 169References 1739 Bacterial Persistence in Biofilms and Antibiotics: Mechanisms Involved 181Anne Jolivet‐Gougeon and Martine Bonnaure‐Mallet9.1 Introduction 1819.2 Reasons for Failure of Antibiotics in Biofilms 1829.2.1 Failure of Antibiotics to Penetrate Biofilm: Active Antibiotics on the Biofilm 1829.2.2 Outer Membrane Vesicles (OMVs) 1839.2.3 Horizontal Transfer of Encoding β‐Lactamase Genes 1849.2.4 Influence of Subinhibitory Concentrations of Antibiotics on Biofilm 1849.2.5 Small Colony Variants (SCVs), Persistence (Persisters), and Toxin–Antitoxin (TA) Systems 1869.2.6 Quorum Sensing: Bacterial Metabolites 1919.2.7 Extracellular DNA 1919.2.8 Nutrient Limitation 1929.2.9 SOS Inducers (Antibiotics and Others) 1929.2.10 Hypermutator Phenotype 1929.2.11 Multidrug Efflux Pumps 1939.3 Usual and Innovative Means to Overcome Biofilm Resistance in Biofilms 1939.3.1 Antibiotics (Bacteriocins) Natural and Synthetic Molecules: Phages 1949.3.2 Efflux Pump Inhibitors 1959.3.3 Anti‐Persisters: Quorum‐Sensing Inhibitors 1959.3.4 Enzymes 1969.3.5 Electrical Methods 1969.3.6 Photodynamic Therapy 1969.4 Conclusion 197Acknowledgments 197Conflict of Interest 197References 197Part III Socio-Economical Perspectives and Impact of AR 21110 Sources of Antibiotic Resistance: Zoonotic, Human, Environment 213Ivone Vaz‐Moreira, Catarina Ferreira, Olga C. Nunes, and Célia M. Manaia10.1 The Antibiotic Era 21310.2 Intrinsic and Acquired Antibiotic Resistance 21410.3 The Natural Antibiotic Resistome 21510.4 The Contaminant Resistome 21510.5 Evolution of Antibiotics Usage 21610.6 Antibiotic Resistance Evolution 21910.7 Stressors for Antibiotic Resistance 21910.8 Paths of Antibiotic Resistance Dissemination 22110.9 Antibiotic Resistance in Humans and Animals 22410.10 Final Considerations 227References 22811 Antibiotic Resistance: Immunity‐Acquired Resistance: Evolution of Antimicrobial Resistance Among Extended‐Spectrum β‐Lactamases and Carbapenemases in Klebsiella pneumonia and Escherichia coli 239Isabel Carvalho, Nuno Silva, João Carrola, Vanessa Silva, Carol Currie, Gilberto Igrejas, and Patrícia Poeta11.1 Overview of Antibiotic Resistance as a Worldwide Health Problem 23911.2 Objectives 24111.3 Causes of Antimicrobial Resistance 24211.4 Enterobacteriaceae: General Characterization 24311.4.1 Escherichia coli 24311.4.2 Klebsiella pneumoniae 24411.5 Current Antibiotic Resistance Threats 24511.5.1 Carbapenem‐Resistant Enterobacteriaceae 24511.5.2 Extended‐Spectrum β‐Lactamase 24711.6 Consequences and Future Strategies to Brace the Antibiotic Backbone 25011.7 Concluding Remarks and Future Perspectives 251Acknowledgments 252References 25212 Extended‐Spectrum‐β‐Lactamase and Carbapenemase‐Producing Enterobacteriaceae in Food‐Producing Animals in Europe: An Impact on Public Health? 261Nuno Silva, Isabel Carvalho, Carol Currie, Margarida Sousa, Gilberto Igrejas, and Patrícia Poeta12.1 Extended‐Spectrum β‐Lactamase 26112.1.1 ESBL‐Producing Enterobacteriaceae in Food Animals 26212.2 Carbapenemases 26512.3 Concluding Remarks 267References 268Part IV Therapeutic Strategy for Overcoming AR 27513 AR Mechanism‐Based Drug Design 277Mire Zloh13.1 Introduction 27713.2 Drug Design Principles 27913.3 Identification of Novel Targets and Novel Mechanisms of Action 28213.4 Efflux Pump Inhibitors 28613.5 Design of Inhibitors of Drug‐Modifying Enzymes 29413.6 Antimicrobial Peptides 29713.7 Other Approaches to Overcome Bacterial Resistance 29913.8 Conclusion 300References 30014 Antibiotics from Natural Sources 311David J. Newman14.1 Introduction 31114.1.1 The Origin of Microbial Resistance Gene Products 31114.2 Organization of the Following Sections 31214.3 Peptidic Antibiotics (Both Cyclic and Acyclic) 31214.3.1 Tyrocidines, Gramacidins, and Derivatives 31214.3.2 Streptogramins and Derivatives: Cyclic Peptides 31314.3.3 Arylomycins (Lipopeptide and Modification, Preclinical) 31314.3.4 Daptomycin (Cyclic Depsilipopeptide) 31414.3.5 Colistins (Cyclic Peptides with a Lipid Tail) 31514.3.6 Glycopeptides 31714.3.7 Host Defense Peptides 31914.4 β‐Lactams: Development, Activities, and Chemistry 32114.4.1 Combinations with β‐Lactamase Inhibitors 32214.5 Aminoglycosides 32314.5.1 Streptomycin 32314.5.2 Plazomicin 32314.6 Early Tetracyclines: Aureomycin and Terramycin 32414.6.1 Semisynthetic Tetracyclines from 2005 32414.7 Erythromycin Macrolides 32614.7.1 Recent Semisynthetic Macrolides 32614.8 Current Methods of “Discovering Novel Antibiotics” 32814.8.1 Introduction 32814.8.2 Initial Rate‐Limiting Step (Irrespective of Methods) 32814.8.3 Genomic Analyses of Whole Microbes 32914.8.4 Isolated Genomics 32914.8.5 New Sources (and Old Ones?) for Investigation 33114.8.6 “Baiting” for Microbes 33114.8.7 Use of Elicitors 33314.9 Conclusions 33314.9.1 Funding? 33414.9.2 The “Take‐Home Lesson” 334References 33415 Bacteriophage Proteins as Antimicrobials to Combat Antibiotic Resistance 343Hugo Oliveira, Luís D. R. Melo, and Sílvio B. Santos15.1 Introduction 34315.2 Polysaccharide Depolymerases 34615.2.1 Depolymerase Structure 34815.2.2 Depolymerase Classification 34915.2.3 Depolymerase Activity Assessment 35015.2.4 Depolymerases as Antimicrobials 35115.2.5 Remarks on Depolymerases 35515.3 Peptidoglycan‐Degrading Enzymes 35615.3.1 Virion‐Associated Lysins (VALs) 35815.3.2 Gram‐Positive Targeting Endolysins 36515.3.3 Gram‐Negative Targeting Endolysins 37415.4 Holins 38815.4.1 Holin Structure 38815.4.2 Holins as Antimicrobials 38915.4.3 Remarks on Holins 39015.5 Final Considerations 390References 39216 Antibiotic Modification Addressing Resistance 407Haotian Bai and Shu Wang16.1 Chemical Synthesis of New Antibiotics 40716.2 Antibiotic Modification with Targeted Groups 41316.3 Antibiotic Modification with Photo‐Switching Units 41716.4 Antibiotic Modification by Supramolecular Chemistry 42016.5 Antibiotic Modification by Complexed with Other Materials 42316.6 Conclusion 425References 42517 Sensitizing Agents to Restore Antibiotic Resistance 429Anton Gadelii, Karl‐Omar Hassan, and Anders P. Hakansson17.1 Introduction 42917.2 Sensitizing Strategies Directly Targeting Resistance Mechanisms 43017.2.1 Inhibition of β‐Lactamases 43017.2.2 Drug Efflux Pump Inhibitors (EPIs) 43317.3 Sensitizing Strategies Circumventing Resistance Mechanisms 43517.3.1 Manipulating Bacterial Homeostasis 43517.3.2 Cell Wall/Membrane Proteins 43717.3.3 Biofilms and Quorum Sensing 43817.3.4 Persister Cells 44017.3.5 Targeting Nonessential Genes/Proteins 44117.3.6 Bacteriophages 44117.4 Using and Strengthening the Human Immune System Against Resistant Bacteria 44117.4.1 Strengthening Host Immune System Function 44117.4.2 Antimicrobial Peptides (AMPs) 44317.5 Conclusion 443References 44418 Repurposing Antibiotics to Treat Resistant Gram‐Negative Pathogens 453Frank Schweizer18.1 Introduction 45318.2 Anti‐Virulence Strategy 45418.3 Antibiotic Combination Strategy 45418.4 Antibiotic–Antibiotic Combination Approach 45518.5 Antibiotic–Adjuvant Combination Approach 45618.6 β‐Lactam and β‐Lactamase Inhibitor Combination 45618.7 Imipenem–Cilastatin/Relebactam Triple Combination 45718.8 Aspergillomarasmine A 45818.9 Intrinsic Resistance Challenges and Strategies to Overcome Them 45818.10 Repurposing of Hydrophobic Antibiotics with High Molecular Weight by Enhancing Outer Membrane Permeability Using Polybasic Adjuvants 46118.11 Repurposing of Hydrophobic Antibiotics with Large Molecular Weight and Other Antibacterials as Antipseudomonal Agents Using Polybasic Adjuvants 46418.12 Repurposing of Antibiotics as Potent Agents Against MDR GNB 46718.13 Outlook and Conclusions 468References 46819 Nontraditional Medicines for Treatment of Antibiotic Resistance 477Ana Paula Guedes Frazzon, Michele Bertoni Mann, and Jeverson Frazzon19.1 Introduction 47719.2 Antibodies 47819.2.1 Raxibacumab Versus Bacillus anthracis 47819.2.2 Bezlotoxumab Versus Clostridium difficile 47919.2.3 Panobacumab Versus Pseudomonas aeruginosa 47919.2.4 LC10 Versus Staphylococcus aureus 48019.3 Immunomodulators 48119.3.1 Antibodies plus Polymyxins 48119.3.2 Antibodies plus Vitamin D 48219.3.3 Antibodies plus Clavanin 48219.3.4 Antibodies plus Reltecimod 48319.4 Potentiators of Antibiotic Activity 48319.4.1 Antibiotic–Antibiotic Combinations 48419.4.2 Pairing of Antibiotic with Nonantibiotic 48519.5 Bacteriophages 48819.5.1 Life Cycles of Bacteriophages 48819.5.2 Bacteriophage Therapy 48919.5.3 Phage Enzymes 49019.5.4 Concerns About the Application of Phage to Treat Bacteria 49119.6 Therapy with Essential Oils 49119.7 Microbiota‐Based Therapy 49519.7.1 Microbiota Modulation 49519.7.1.1 Probiotics 49619.7.1.2 Prebiotics 49619.7.2 Stool Microbiota Transplant 496Further Reading 49720 Therapeutic Options for Treatment of Infections by Pathogenic Biofilms 503Bruna de Oliveira Costa, Osmar Nascimento Silva, and Octávio Luiz Franco20.1 Introduction 50320.2 Antibiotic Therapy for the Treatment of Pathogenic Biofilms 50420.2.1 Monotherapy 50420.2.2 Antibiotic Combination Therapy 50520.3 New Findings for the Treatment of Pathogenic Biofilms 50720.3.1 AMPs Applied to Treatment Pathogenic Biofilms 50720.3.2 Bacteriophage Therapy Anti‐Biofilm 51420.3.3 Nanotechnology Applied to the Treatment of Pathogenic Biofilms 51720.4 Conclusion and Future Directions 519References 520Part V Strategies to Prevent the Spread of AR 53321 Rapid Analytical Methods to Identify Antibiotic‐Resistant Bacteria 535John B. Sutherland, Fatemeh Rafii, Jackson O. Lay, Jr., and Anna J. Williams21.1 Introduction 53521.2 Standard Methods for Antibiotic Sensitivity Testing 53621.3 Rapid Cultural Methods 53721.4 Rapid Serological Methods 54021.5 Rapid Molecular (Genetic) Methods 54021.6 Mass Spectrometric Methods 54521.7 Flow Cytometric Methods 54921.8 Conclusions 550Acknowledgments 553References 55322 Effective Methods for Disinfection and Sterilization 567Lucía Fernández, Diana Gutiérrez, Beatriz Martínez, Ana Rodríguez, and Pilar García22.1 Introduction 56722.2 Disinfection and Sterilization: Methods and Factors Involved in Their Efficacy 56922.2.1 Methods of Sterilization and Disinfection 57022.2.2 Factors Influencing Disinfection and Sterilization Efficacy 57022.3 Resistance to Disinfectants 57122.3.1 Molecular Mechanisms of Biocide Resistance 57122.3.2 Biofilms 57222.3.3 Cross‐Resistance Between Antibiotics and Disinfectants 57422.4 New Technologies as Alternatives to Classical Disinfectants 57522.4.1 Chemical and Physical Disinfectants 57522.4.2 Antimicrobial Surfaces 57822.4.3 Biological Disinfectants 57822.5 Current Legislation 57922.6 Conclusions 581References 58223 Strategies to Prevent the Spread of Antibiotic Resistance: Understanding the Role of Antibiotics in Nature and Their Rational Use 589Rustam Aminov23.1 Introduction 58923.2 Agriculture as the Largest Consumer of Antimicrobials 59023.3 Antimicrobials and Antimicrobial Resistance 59123.4 First‐Generation Tetracyclines: Discovery and Usage 59223.5 Tetracycline Resistance Mechanisms 59323.6 Phylogeny of Tetracycline Resistance Genes 59323.7 Second‐Generation Tetracyclines 59523.8 Third‐Generation Tetracyclines 59523.9 Resistance to Third‐Generation Tetracyclines 59623.10 Other Potential Resistance Mechanisms Toward Third‐Generation Tetracyclines 59723.11 Evolutionary Aspect of tet(X) 59823.12 Ecological Aspects of tet(X) 59923.13 Antibiotics and Antibiotic Resistance as Integral Parts of Microbial Diversity 60223.14 The Role of Antibiotics in Natural Ecosystems 60423.15 Low‐Dose Antibiotics: Phenotypic Effects 60523.16 Low‐Dose Antibiotics: Genetic Effects 60623.17 Regulation of Antibiotic Synthesis in Antibiotic Producers 60823.18 Convergent Evolution of Antibiotics as Signaling Molecules 61023.19 Carbapenems: Convergent Evolution and Regulation in Different Bacteria 61123.20 Antibiotics and Antibiotic Resistance: Environmental and Anthropogenic Contexts 61423.21 Conclusions 615Conflict of Interest 616References 616Part VI Public Policy 63724 Strategies to Reduce or Eliminate Resistant Pathogens in the Environment 639Johan Bengtsson‐Palme and Stefanie Heß24.1 Introduction 63924.2 Sources of Resistant Bacteria in the Environment 64024.3 Sewage and Wastewater 64124.3.1 Sewage Treatment Plants 64124.3.2 Non‐Treated Sewage 64324.3.3 Industrial Wastewater Effluents 64324.3.4 Environmental Antibiotic Resistance is a Poverty Problem 64424.4 Agriculture 64624.4.1 Intensive, Large‐Scale Animal Husbandry 64624.4.2 Manure Application 64724.4.3 Agriculture in Developing Countries 64724.4.4 Aquaculture 64824.5 De Novo Resistance Selection 64924.6 Relevant Risk Scenarios 64924.7 Management Options 65324.7.1 Possible Interventions on the Level of Releases of Resistant Bacteria 65324.7.2 Restricting Transmission of Resistant Bacteria from the Environment 65724.7.3 Better Agriculture Practices to Sustain the Lifespans of Antibiotics 65824.7.4 Limiting Selection for Resistance in the Environment 65924.8 Final Remarks 661Acknowledgments 662Conflict of Interest 662References 662Index 675