Cover
List of Contributors
Preface
1. References
About the Editors
Part I: Current Antibiotics and Their Mechanism of Action
1. 1 Resistance to Aminoglycosides
  1. 1.1 Aminoglycosides as Antimicrobial Drugs
  2. 1.2 Mechanisms of Resistance
  3. 1.3 Development of New AGAs: The Potential of Glycomics
  4. 1.4 Influence of the Human Microbiome in Aminoglycoside Resistance
  5. 1.5 Conclusions and Outlook
  6. Acknowledgments
  7. References
2. 2 Mechanisms of Action and of Resistance to Quinolones
  1. 2.1 Introduction
  2. 2.2 Mechanism of Action of Quinolones
  3. 2.3 Mutations in the Genes Encoding the Targets of Quinolones
  4. 2.4 Multidrug Efflux Pumps and Quinolone Resistance
  5. 2.5 Transferable Quinolone Resistance
  6. 2.6 Stenotrophomonas maltophilia and Its Uncommon Mechanisms of Resistance to Quinolones
  7. Acknowledgments
  8. References
3. 3 Beta‐Lactams
  1. 3.1 Introduction
  2. 3.2 Chemical Structure
  3. 3.3 Classification and Spectrum of Activity
  4. 3.4 Mechanism of Action
  5. 3.5 Activity of Beta‐Lactams Against Multiresistant Bacteria
  6. 3.6 Conclusions
  7. References
4. 4 Glycopeptide Antibiotics
  1. 4.1 Introduction
  2. 4.2 Naturally Occurring Glycopeptide Antibiotics
  3. 4.3 Mechanism of Action of Glycopeptide Antibiotics
  4. 4.4 Resistance to Glycopeptides
  5. 4.5 Second‐Generation Glycopeptides
  6. 4.6 Strategies to Overcome Resistance to Glycopeptides
  7. 4.7 Glycopeptides Under Clinical Trials
  8. 4.8 Glycopeptide Antibiotics: The Challenges
  9. References
5. 5 Current Macrolide Antibiotics and Their Mechanisms of Action
  1. 5.1 Introduction
  2. 5.2 Structure of Macrolides
  3. 5.3 Macrolide Mechanisms of Action
  4. 5.4 Clinical Use of Macrolides
  5. 5.5 Next‐Generation Macrolides and Future Use
  6. References
Part II: Mechanism of Antibiotic Resistance
1. 6 Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of β‐Lactamases
  1. 6.1 Introduction
  2. 6.2 Structure of the Protein Globule of TEM‐Type β‐Lactamases: Catalytic and Mutated Residues
  3. 6.3 Effect of the Key Mutations on Activity of TEM‐Type β‐Lactamases
  4. 6.4 Effect of Secondary Mutations on the Stability of TEM‐Type β‐Lactamases
  5. 6.5 Conclusions
  6. Abbreviations
  7. References
2. 7 Acquired Resistance from Gene Transfer
  1. 7.1 Introduction
  2. 7.2 Horizonal Gene Transfer: A Brief Overview
  3. 7.3 Conjugative Transfer Mechanisms
  4. 7.4 Antibiotic Resistances and Their Transfer
  5. 7.5 Nanotubes Involved in Acquisition of Antibiotic Resistances
  6. 7.6 Conclusions and Outlook
  7. Abbreviations
  8. References
3. 8 Antimicrobial Efflux Pumps
  1. 8.1 Bacterial Antimicrobial Efflux Pumps
  2. References
4. 9 Bacterial Persistence in Biofilms and Antibiotics
  1. 9.1 Introduction
  2. 9.2 Reasons for Failure of Antibiotics in Biofilms
  3. 9.3 Usual and Innovative Means to Overcome Biofilm Resistance in Biofilms
  4. 9.4 Conclusion
  5. Acknowledgments
  6. Conflict of Interest
  7. References
Part III: Socio‐Economical Perspectives and Impact of AR
1. 10 Sources of Antibiotic Resistance
  1. 10.1 The Antibiotic Era
  2. 10.2 Intrinsic and Acquired Antibiotic Resistance
  3. 10.3 The Natural Antibiotic Resistome
  4. 10.4 The Contaminant Resistome
  5. 10.5 Evolution of Antibiotics Usage
  6. 10.6 Antibiotic Resistance Evolution
  7. 10.7 Stressors for Antibiotic Resistance
  8. 10.8 Paths of Antibiotic Resistance Dissemination
  9. 10.9 Antibiotic Resistance in Humans and Animals
  10. 10.10 Final Considerations
  11. References
2. 11 Antibiotic Resistance
  1. 11.1 Overview of Antibiotic Resistance as a Worldwide Health Problem
  2. 11.2 Objectives
  3. 11.3 Causes of Antimicrobial Resistance
  4. 11.4 Enterobacteriaceae: General Characterization
  5. 11.5 Current Antibiotic Resistance Threats
  6. 11.6 Consequences and Future Strategies to Brace the Antibiotic Backbone
  7. 11.7 Concluding Remarks and Future Perspectives
  8. Acknowledgments
  9. References
3. 12 Extended‐Spectrum‐β‐Lactamase and Carbapenemase‐Producing Enterobacteriaceae in Food‐Producing Animals in Europe
  1. 12.1 Extended‐Spectrum β‐Lactamase
  2. 12.2 Carbapenemases
  3. 12.3 Concluding Remarks
  4. References
Part IV: Therapeutic Strategy for Overcoming AR
1. 13 AR Mechanism‐Based Drug Design
  1. 13.1 Introduction
  2. 13.2 Drug Design Principles
  3. 13.3 Identification of Novel Targets and Novel Mechanisms of Action
  4. 13.4 Efflux Pump Inhibitors
  5. 13.5 Design of Inhibitors of Drug‐Modifying Enzymes
  6. 13.6 Antimicrobial Peptides
  7. 13.7 Other Approaches to Overcome Bacterial Resistance
  8. 13.8 Conclusion
  9. References
2. 14 Antibiotics from Natural Sources
  1. 14.1 Introduction
  2. 14.2 Organization of the Following Sections
  3. 14.3 Peptidic Antibiotics (Both Cyclic and Acyclic)
  4. 14.4 β‐Lactams: Development, Activities, and Chemistry
  5. 14.5 Aminoglycosides
  6. 14.6 Early Tetracyclines: Aureomycin and Terramycin
  7. 14.7 Erythromycin Macrolides
  8. 14.8 Current Methods of “Discovering Novel Antibiotics”
  9. 14.9 Conclusions
  10. References
3. 15 Bacteriophage Proteins as Antimicrobials to Combat Antibiotic Resistance
  1. 15.1 Introduction
  2. 15.2 Polysaccharide Depolymerases
  3. 15.3 Peptidoglycan‐Degrading Enzymes
  4. 15.4 Holins
  5. 15.5 Final Considerations
  6. References
4. 16 Antibiotic Modification Addressing Resistance
  1. 16.1 Chemical Synthesis of New Antibiotics
  2. 16.2 Antibiotic Modification with Targeted Groups
  3. 16.3 Antibiotic Modification with Photo‐Switching Units
  4. 16.4 Antibiotic Modification by Supramolecular Chemistry
  5. 16.5 Antibiotic Modification by Complexed with Other Materials
  6. 16.6 Conclusion
  7. References
5. 17 Sensitizing Agents to Restore Antibiotic Resistance
  1. 17.1 Introduction
  2. 17.2 Sensitizing Strategies Directly Targeting Resistance Mechanisms
  3. 17.3 Sensitizing Strategies Circumventing Resistance Mechanisms
  4. 17.4 Using and Strengthening the Human Immune System Against Resistant Bacteria
  5. 17.5 Conclusion
  6. References
6. 18 Repurposing Antibiotics to Treat Resistant Gram‐Negative Pathogens
  1. 18.1 Introduction
  2. 18.2 Anti‐Virulence Strategy
  3. 18.3 Antibiotic Combination Strategy
  4. 18.4 Antibiotic–Antibiotic Combination Approach
  5. 18.5 Antibiotic–Adjuvant Combination Approach
  6. 18.6 β‐Lactam and β‐Lactamase Inhibitor Combination
  7. 18.7 Imipenem–Cilastatin/Relebactam Triple Combination
  8. 18.8 Aspergillomarasmine A
  9. 18.9 Intrinsic Resistance Challenges and Strategies to Overcome Them
  10. 18.10 Repurposing of Hydrophobic Antibiotics with High Molecular Weight by Enhancing Outer Membrane Permeability Using Polybasic Adjuvants
  11. 18.11 Repurposing of Hydrophobic Antibiotics with Large Molecular Weight and Other Antibacterials as Antipseudomonal Agents Using Polybasic Adjuvants
  12. 18.12 Repurposing of Antibiotics as Potent Agents Against MDR GNB
  13. 18.13 Outlook and Conclusions
  14. References
7. 19 Nontraditional Medicines for Treatment of Antibiotic Resistance
  1. 19.1 Introduction
  2. 19.2 Antibodies
  3. 19.3 Immunomodulators
  4. 19.4 Potentiators of Antibiotic Activity
  5. 19.5 Bacteriophages
  6. 19.6 Therapy with Essential Oils
  7. 19.7 Microbiota‐Based Therapy
  8. Further Reading
8. 20 Therapeutic Options for Treatment of Infections by Pathogenic Biofilms
  1. 20.1 Introduction
  2. 20.2 Antibiotic Therapy for the Treatment of Pathogenic Biofilms
  3. 20.3 New Findings for the Treatment of Pathogenic Biofilms
  4. 20.4 Conclusion and Future Directions
  5. References
Part V: Strategies to Prevent the Spread of AR
1. 21 Rapid Analytical Methods to Identify Antibiotic‐Resistant Bacteria
  1. 21.1 Introduction
  2. 21.2 Standard Methods for Antibiotic Sensitivity Testing
  3. 21.3 Rapid Cultural Methods
  4. 21.4 Rapid Serological Methods
  5. 21.5 Rapid Molecular (Genetic) Methods
  6. 21.6 Mass Spectrometric Methods
  7. 21.7 Flow Cytometric Methods
  8. 21.8 Conclusions
  9. Acknowledgments
  10. References
2. 22 Effective Methods for Disinfection and Sterilization
  1. 22.1 Introduction
  2. 22.2 Disinfection and Sterilization: Methods and Factors Involved in Their Efficacy
  3. 22.3 Resistance to Disinfectants
  4. 22.4 New Technologies as Alternatives to Classical Disinfectants
  5. 22.5 Current Legislation
  6. 22.6 Conclusions
  7. References
3. 23 Strategies to Prevent the Spread of Antibiotic Resistance
  1. 23.1 Introduction
  2. 23.2 Agriculture as the Largest Consumer of Antimicrobials
  3. 23.3 Antimicrobials and Antimicrobial Resistance
  4. 23.4 First‐Generation Tetracyclines: Discovery and Usage
  5. 23.5 Tetracycline Resistance Mechanisms
  6. 23.6 Phylogeny of Tetracycline Resistance Genes
  7. 23.7 Second‐Generation Tetracyclines
  8. 23.8 Third‐Generation Tetracyclines
  9. 23.9 Resistance to Third‐Generation Tetracyclines
  10. 23.10 Other Potential Resistance Mechanisms Toward Third‐Generation Tetracyclines
  11. 23.11 Evolutionary Aspect of tet(X)
  12. 23.12 Ecological Aspects of tet(X)
  13. 23.13 Antibiotics and Antibiotic Resistance as Integral Parts of Microbial Diversity
  14. 23.14 The Role of Antibiotics in Natural Ecosystems
  15. 23.15 Low‐Dose Antibiotics: Phenotypic Effects
  16. 23.16 Low‐Dose Antibiotics: Genetic Effects
  17. 23.17 Regulation of Antibiotic Synthesis in Antibiotic Producers
  18. 23.18 Convergent Evolution of Antibiotics as Signaling Molecules
  19. 23.19 Carbapenems: Convergent Evolution and Regulation in Different Bacteria
  20. 23.20 Antibiotics and Antibiotic Resistance: Environmental and Anthropogenic Contexts
  21. 23.21 Conclusions
  22. Conflict of Interest
  23. References
Part VI: Public Policy
1. 24 Strategies to Reduce or Eliminate Resistant Pathogens in the Environment
  1. 24.1 Introduction
  2. 24.2 Sources of Resistant Bacteria in the Environment
  3. 24.3 Sewage and Wastewater
  4. 24.4 Agriculture
  5. 24.5 De Novo Resistance Selection
  6. 24.6 Relevant Risk Scenarios
  7. 24.7 Management Options
  8. 24.8 Final Remarks
  9. Acknowledgments
  10. Conflict of Interest
  11. References
Index
End User License Agreement

List of Tables

Chapter 1
1. Table 1.1 Overview of major aminoglycoside antibiotics (AGAs) and their disti...
Chapter 3
1. Table 3.1 Combination of beta‐lactamase inhibitor with a beta‐lactam antibiot...
2. Table 3.2 Bacteria and resistance considered for each level of priority as we...
Chapter 4
1. Table 4.1 Clinical use of glycopeptide antibiotics.
Chapter 15
1. Table 15.1 Depolymerase as antimicrobials.
2. Table 15.2 Virion‐associated lysins (VALs) as antimicrobials.
3. Table 15.3 Gram‐positive targeting endolysins as antimicrobials.
4. Table 15.4 Gram‐negative targeting endolysins as antimicrobials.
Chapter 19
1. Table 19.1 Mechanism of action and dermatological use of some essential oils.
Chapter 20
1. Table 20.1 Natural peptides with anti‐biofilm activity.
2. Table 20.2 Examples of synthetic peptides with anti‐biofilm properties.
Chapter 21
1. Table 21.1 A summary of rapid methods for analysis of antibiotic‐resistant ba...
Chapter 24
1. Table 24.1 Strategies to reduce the flow of antibiotics and resistant bacteri...

List of Illustrations

Chapter 1
1. Figure 1.1 Core structural elements of the aminoglycosides and examples of c...
2. Figure 1.2 Schematic representation of the mode of action of AGAs in the bac...
3. Figure 1.3 Representative crystal structures of the three types of AMEs and ...
4. Figure 1.4 Examples of chemical approaches to prepare covalent aminoglycosid...
Chapter 3
1. Figure 3.1 The β‐lactam core structures. (a) A penam. (b) A carbapenem. (c) ...
2. Figure 3.2 Molecule of 6‐aminopenicillanic acid. Circle: amino group in posi...
3. Figure 3.3 7‐Aminocephalosporanic acid, core structure of cephalosporins.
4. Figure 3.4 Core structure of cephamycins. Circle: methoxy group in position ...
5. Figure 3.5 Aztreonam molecule.
6. Figure 3.6 Carbapenem core structure. Circle: 6‐trans‐hydroxyethyl group.
7. Figure 3.7 A: Peptidoglycan structure. B: Examples of cross‐linkage and inte...
Chapter 4
1. Figure 4.1 (a) Natural and (b) semisynthetic glycopeptide antibiotics approv...
2. Figure 4.2 (a) Vancomycin binds to the D‐Ala‐D‐Ala terminal through five H‐b...
3. Figure 4.3 Glycopeptide derivatives with enhanced binding affinity to mutate...
4. Figure 4.4 Multivalent analogues to increase activity through enhanced bindi...
5. Figure 4.5 Vancomycin derivatives with lipophilic moieties to enhance activi...
6. Figure 4.6 Cationic lipophilic vancomycin derivatives with membrane disrupti...
7. Figure 4.7 Vancomycin–dipicolyl derivative that interacts with the pyrophosp...
8. Figure 4.8 Glycopeptide‐based new molecules under clinical trials.
Chapter 5
1. Figure 5.1 Erythromycin structure.
Chapter 6
1. Figure 6.1 The secondary structure of β‐lactamase TEM‐1 (PDB ID 1ERO (Ness e...
2. Figure 6.2 Schematic representation of the structural fold of β‐lactamase TE...
3. Figure 6.3 Scheme of β‐lactam antibiotic hydrolysis by β‐lactamase TEM‐1 (a)...
4. Figure 6.4 Distribution of combinations of mutations in TEM‐type β‐lactamase...
5. Figure 6.5 Single key mutations and their combinations in TEM‐type β‐lactama...
6. Figure 6.6 Relative catalytic efficiency (k_cat/K_M) of TEM ESBLs and CMT β‐la...
7. Figure 6.7 Relative Ki of IRT and CMT TEM‐type β‐lactamases compared with K_i
Chapter 7
1. Figure 7.1 Common classes of antibiotic drugs and their targets. Antibiotics...
2. Figure 7.2 Mechanisms of horizontal gene transfer. Horizontal gene transfer ...
3. Figure 7.3 Transfer mechanism of conjugative plasmids. Upon a signal from th...
4. Figure 7.4 Transfer mechanism of integrative conjugative elements (ICEs). Wi...
Chapter 9
1. Figure 9.1 Interrelation between activation of the toxin–antitoxin (TA) syst...
2. Figure 9.2 Example of persister formation under starvation in a toxin–antito...
Chapter 10
1. Figure 10.1 Consumption of antibiotics in humans and food‐producing animals ...
2. Figure 10.2 Antibiotic resistance dissemination pathways.
Chapter 11
1. Figure 11.1 Main mechanisms of antibiotic resistance: modification of the ta...
2. Figure 11.3 Wide distribution of extended‐spectrum β‐lactamase‐producing Esc...
Chapter 12
1. Figure 12.1 Schematic representation of studies reporting the presence of th...
Chapter 13
1. Figure 13.1 Schematic representation of the mechanisms of resistance in Gram...
2. Figure 13.2 Overview of the methods used in the computer‐aided design of ant...
3. Scheme 13.1 IS‐130 scaffold.
4. Figure 13.3 A complete step‐by‐step flow of different methodologies to ident...
5. Scheme 13.2 Structures of some well‐known EPIs.
6. Figure 13.4 Scheme for the development of the pharmacophore model of the Sta...
7. Figure 13.5 Tetracycline in the multi‐binding sites within the binding proto...
8. Figure 13.6 Schematic outline of the methods used for in silico inhibitor de...
9. Figure 13.7 Highest interaction energy complexes between MDR inhibitors and ...
10. Figure 13.8 Structure‐based design of broad‐spectrum MBL inhibitors. (a) Kno...
Chapter 15
1. Figure 15.1 The phage replication cycle. Phage adsorbs to the bacterial cell...
2. Figure 15.2 Phage‐derived proteins with high potential as antimicrobials, th...
3. Figure 15.3 Distribution of the different polysaccharide depolymerase classe...
4. Figure 15.4 Illustration of the peptidoglycan bonds cleaved by enzymatic cat...
5. Figure 15.5 Different molecular arrangements possibilities of phage endolysi...
Chapter 16
1. Scheme 16.1 Chemical structures of (1)–(7).
2. Scheme 16.2 Chemical structures of (8)–(10).
3. Scheme 16.3 Chemical structures of (11)–(16), including vancomycin, chloroer...
4. Scheme 16.4 The chemical structure of (17) of the synthesized glycopeptide a...
5. Scheme 16.5 Chemical structures of (18)–(20).
6. Scheme 16.6 Schematic illumination of the resistance acquisition pathways an...
7. Scheme 16.7 Chemical structures of (21) and (22).
8. Scheme 16.8 Schematic illustration of the antibody–antibiotic conjugate.
9. Scheme 16.9 Chemical structures of (23)–(26).
10. Scheme 16.10 Chemical structures of (27)–(31).
11. Scheme 16.11 Chemical structures of (32)–(37).
12. Scheme 16.12 The plate photographs of Staphylococcus aureus treated with DDB...
13. Scheme 16.13 Schematic illumination of the preparation process of (a) Van⊄SG...
14. Scheme 16.14 Schematic illumination of the synthesis process of aminoglycosi...
Chapter 17
1. Figure 17.1 Strategies to sensitize bacteria to antibiotics. A simple sketch...
Chapter 18
1. Figure 18.1 Structures of polymyxins (1) and (2) and polymyxin‐derived antib...
2. Figure 18.2 Structure of non‐polymyxin‐based outer membrane permeabilizers....
3. Figure 18.3 Polybasic compounds destabilize the outer membrane of Gram‐negat...
4. Figure 18.4 Structure of hydrophobic antibiotics with large molecular weight...
5. Figure 18.5 Structure of tobramycin‐based antibiotic adjuvants that potentia...
6. Figure 18.6 Structure of non‐polymyxin or non‐tobramycin‐based antibiotic ad...
Chapter 20
1. Figure 20.1 Mechanisms of anti‐biofilm action of AMPs. (1) Inhibition of bio...
2. Figure 20.2 Mechanisms for biofilm degradation by phages. (1) Infection of t...
Chapter 22
1. Figure 22.1 Methods of disinfection/sterilization according to the Spaulding...
2. Figure 22.2 Mechanisms of adaptive resistance to disinfectants. (a) Examples...
Chapter 24
1. Figure 24.1 Access to safe drinking water (a) and sanitation services (b) di...
2. Figure 24.2 Overview of where in the environment it would be possible to int...

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Library of Congress Cataloging‐in‐Publication Data
Names: Capelo‐Martinez, Jose‐Luis, editor. | Igrejas, Gilberto, editor.
Title: Antibiotic drug resistance / edited by Jose‐Luis Capelo Martinez, Gilberto Igrejas.
Description: First edition. | Hoboken, NJ : Wiley, 2019. | Includes bibliographical references and index. |
Identifiers: LCCN 2019016039 (print) | LCCN 2019017013 (ebook) | ISBN 9781119282532 (Adobe PDF) | ISBN 9781119282556 (ePub) | ISBN 9781119282525 (hardback)
Subjects: | MESH: Anti‐Bacterial Agents | Drug Resistance, Bacterial
Classification: LCC RM267 (ebook) | LCC RM267 (print) | NLM QV 350 | DDC 615.7/922–dc23
LC record available at https://lccn.loc.gov/2019016039

Cover image: Courtesy of Mathieu F. Chellat, Luka Raguž and Rainer Riedl
Cover design by Wiley

List of Contributors

Teresa Alarcón
Department of Microbiology, Hospital Universitario La Princesa
Instituto de Investigación Sanitaria Princesa
Madrid, Spain

Department of Preventive Medicine, Public Health and Microbiology, Medical School
Autonomous University of Madrid
Madrid, Spain

Egorov Alexey
Department of Chemistry
M.V. Lomonosov Moscow State University
Moscow, Russia

Rustam Aminov
School of Medicine, Medical Sciences and Nutrition
University of Aberdeen
Aberdeen, UK

Institute of Fundamental Medicine and Biology
Kazan Federal University
Kazan, Russia

Haotian Bai
Institute of Chemistry
Chinese Academy of Sciences
Beijing, P. R. China

Luz Balsalobre
Department of Microbiology, Hospital Universitario La Princesa
Instituto de Investigación Sanitaria Princesa
Madrid, Spain

Johan Bengtsson‐Palme
Department of Infectious Diseases
Institute of Biomedicine, The Sahlgrenska Academy
University of Gothenburg
Gothenburg, Sweden

Centre for Antibiotic Resistance Research (CARe)
University of Gothenburg
Gothenburg, Sweden

Wisconsin Institute of Discovery
University of Wisconsin‐Madison
Madison, WI, USA

Ana Blanco
Department of Microbiology
Hospital Universitario La Princesa
Instituto de Investigación Sanitaria Princesa
Madrid, Spain

Martine Bonnaure‐Mallet
Univ Rennes, INSERM, INRA, CHU Rennes Institut NUMECAN (Nutrition Metabolisms and Cancer) Rennes, France

Teaching Hospital of Rennes
Rennes, France

João Carrola
Centre for the Research and Technology of Agro‐Environmental and Biological Sciences (CITAB), University of Trás‐os‐Montes and Alto Douro, Vila Real, Portugal

Ana Luísa Carvalho
UCIBIO‐REQUIMTE, Departamento de Química
Faculdade de Ciências e Tecnologia
Universidade NOVA de Lisboa
Caparica, Portugal

Isabel Carvalho
Department of Veterinary Sciences, Department of Genetics andBiotechnology, Functional Genomics andProteomics Unit, MicroART‐ Antibiotic Resistance Team, University of Trás‐os‐Montes and Alto Douro, Vila Real, Portugal; Laboratory Associated for Green Chemistry (LAQV‐REQUIMTE), New University of Lisbon Monte da Caparica, Portugal;

Viviana G. Correia
UCIBIO‐REQUIMTE, Departamento de Química
Faculdade de Ciências e Tecnologia
Universidade NOVA de Lisboa
Caparica, Portugal

Carol Currie
Moredun Research Institute
Pentlands Science Park
Penicuik, Scotland, UK

Bruna de Oliveira Costa
S‐Inova Biotech, Programa de Pós‐Graduação em Biotecnologia
Universidade Católica Dom Bosco
Campo Grande MS, Brazil

Lucía Fernández
Instituto de Productos Lácteos de Asturias (IPLA‐CSIC)
Villaviciosa, Spain

Catarina Ferreira
Universidade Católica Portuguesa
CBQF – Centro de Biotecnologia e Química Fina
Laboratório Associado, Escola Superior de Biotecnologia
Porto, Portugal

Octávio Luiz Franco
S‐Inova Biotech, Programa de Pós‐Graduação em Biotecnologia
Universidade Católica Dom Bosco
Campo Grande, MS, Brazil

Centro de Análises Proteômicas e Bioquímicas
Programa de Pós‐Graduação em Ciências Genômicas e Biotecnologia
Universidade Católica de Brasília
Brasília, DF, Brazil
Faculdade de Medicina
Programa de Pós‐Graduação em Patologia Molecular
Universidade de Brasília
Brasília, DF, Brazil

Ana Paula Guedes Frazzon
Federal University of Rio Grande do Sul
Porto Alegre, Brazil

Jeverson Frazzon
Federal University of Rio Grande do Sul
Porto Alegre, Brazil

Anton Gadelii
Division of Experimental Infection Medicine
Department of Translational Medicine
Lund University
Malmö, Sweden

Pilar García
Instituto de Productos Lácteos de Asturias (IPLA‐CSIC)
Villaviciosa, Spain

Elisabeth Grohmann
Life Sciences and Technology
Beuth University of Applied Sciences Berlin, Berlin, Germany

Diana Gutiérrez
Instituto de Productos Lácteos de Asturias (IPLA‐CSIC)
Villaviciosa, Spain

Anders P. Hakansson
Division of Experimental Infection Medicine
Department of Translational Medicine
Lund University
Malmö, Sweden

Jayanta Haldar
Antimicrobial Research Laboratory, New Chemistry Unit and School of Advanced Materials, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India

Karl‐Omar Hassan
Division of Experimental Infection Medicine
Department of Translational Medicine
Lund University
Malmö, Sweden

Stefanie Heß
Department of Microbiology
University of Helsinki
Helsinki, Finland

Gilberto Igrejas
Department of Genetics and Biotechnology, Functional Genomics and Proteomics Unit, University of Trás‐os‐Montes and Alto Douro
Vila Real, Portugal

Anne Jolivet‐Gougeon
Univ Rennes, INSERM, INRA, CHU Rennes
Institut NUMECAN (Nutrition Metabolisms and Cancer)
Rennes, France
Teaching Hospital of Rennes
Rennes, France

Verena Kohler
Institute of Molecular Biosciences
University of Graz
Graz, Austria
Department of Molecular Biosciences, The Wenner‐Gren Institute Stockholm University, Stockholm, Sweden

Jackson O. Lay, Jr.
Department of Chemistry and Biochemistry
University of Arkansas
Fayetteville, AR, USA

S. Lohsen
School of Medicine
Emory University
Atlanta, USA

Célia M. Manaia
Universidade Católica Portuguesa
CBQF ‐ Centro de Biotecnologia e Química Fina
Laboratório Associado, Escola Superior de Biotecnologia
Porto, Portugal

Michele Bertoni Mann
Federal University of Rio Grande do Sul
Porto Alegre, Brazil

Ulyashova Mariya
Department of Chemistry
M.V. Lomonosov Moscow State University
Moscow, Russia

Beatriz Martínez
Instituto de Productos Lácteos de Asturias (IPLA‐CSIC)
Villaviciosa, Spain

José L. Martínez
Departamento de Biotecnología Microbiana
Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC)
Madrid, Spain

Rubtsova Maya
Department of Chemistry
M.V. Lomonosov Moscow State University
Moscow, Russia

Luís D. R. Melo
Centre of Biological Engineering (CEB)
Laboratório de Investigação em Biofilmes Rosário Oliveira (LIBRO)
University of Minho
Braga, Portugal

David J. Newman
Newman Consulting LLC
Wayne, PA, USA

Olga C. Nunes
LEPABE – Laboratory for Process Engineering, Environment, Biotechnology and Energy
Faculdade de Engenharia
Universidade do Porto
Porto, Portugal

Hugo Oliveira
Centre of Biological Engineering (CEB)
Laboratório de Investigação em Biofilmes Rosário Oliveira (LIBRO)
University of Minho
Braga, Portugal

Angelina S. Palma
UCIBIO‐REQUIMTE
Departamento de Química
Faculdade de Ciências e Tecnologia
Universidade NOVA de Lisboa
Caparica, Portugal

Benedita A. Pinheiro
UCIBIO‐REQUIMTE
Departamento de Química
Faculdade de Ciências e Tecnologia
Universidade NOVA de Lisboa
Caparica, Portugal

Patrícia Poeta
Microbiology and Antibiotic Resistance Team (MicroART), Department of Veterinary Sciences, University of Trás‐os‐Montes and Alto Douro, Vila Real, Portugal; Laboratory Associated for Green Chemistry (LAQV‐REQUIMTE), New University of Lisbon, Monte da Caparica, Portugal; New University of Lisbon, Monte da Caparica, Portugal

Fatemeh Rafii
National Center for Toxicological Research
U.S. Food and Drug Administration
Jefferson, AR, USA

Ana Rodríguez
Instituto de Productos Lácteos de Asturias (IPLA‐CSIC)
Villaviciosa, Spain

Sílvio B. Santos
Centre of Biological Engineering (CEB)
Laboratório de Investigação em Biofilmes Rosário Oliveira (LIBRO)
University of Minho
Braga, Portugal

Paramita Sarkar
Antimicrobial Research Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India

Frank Schweizer
Department of Chemistry
University of Manitoba
Winnipeg, Canada

Nuno Silva
Moredun Research Institute
Pentlands Science Park
Penicuik, Scotland, UK

Osmar Nascimento Silva
S‐Inova Biotech, Programa de Pós‐Graduação em Biotecnologia
Universidade Católica Dom Bosco
Campo Grande, MS, Brazil

Vanessa Silva
Microbiology and Antibiotic Resistance Team (MicroART), Department of Veterinary Sciences, Department of Genetics and Biotechnology, Functional Genomics and Proteomics Unit, University of Trás‐os‐Montes and Alto Douro, Vila Real, Portugal; Laboratory Associated for Green Chemistry (LAQV‐REQUIMTE), New University of Lisbon, Monte da Caparica, Portugal New University of Lisbon, Monte da Caparica, Portugal

Margarida Sousa
Department of Veterinary Sciences, Department of Genetic and Biotechnology, Functional Genomics and Proteomics Unit
University of Trás‐os‐Montes and Alto Douro
Vila Real, Portugal

D.S. Stephens
School of Medicine
Emory University
Atlanta, GA, USA

John B. Sutherland
National Center for Toxicological Research
U.S. Food and Drug Administration
Jefferson, AR, USA

Ankita Vaishampayan
Life Sciences and Technology
Beuth University of Applied Sciences Berlin
Berlin, Germany

Manuel F. Varela
Eastern New Mexico University
Portales, NM, USA

Ivone Vaz‐Moreira
Universidade Católica Portuguesa
CBQF – Centro de Biotecnologia e Química Fina
Laboratório Associado, Escola Superior de Biotecnologia
Porto, Portugal

LEPABE – Laboratory for Process Engineering, Environment, Biotechnology and Energy
Faculdade de Engenharia
Universidade do Porto
Porto, Portugal

Shu Wang
Institute of Chemistry, Chinese Academy of Sciences
Beijing, P. R. China

Anna J. Williams
National Center for Toxicological Research
U.S. Food and Drug Administration
Jefferson, Arkansas, USA

Mire Zloh
UCL School of Pharmacy
University College London
London, UK

Preface

In the fight to survive, bacteria have been able to find their own path to succeed despite what may be considered their worst‐case evolutionary scenario, the advent of the antibiotic era. Bacterial resistance to antibiotics has reached levels of success unexpectedly 20 years ago. Some bacteria can resist, literally, everything human kind has invented to fight them. The situation is worsening as the bacteria causing pneumonia, tuberculosis, gonorrhea, and salmonellosis are becoming multiresistant to all known antibiotics. For humans, this problem is having a tremendous effect on our society, regardless of gender, age, or country, because the cost of medical care is increasingly high due to longer hospital stays and the need of sophisticated and expensive new drugs. There is an additional threat for immunodepressed patients who cannot survive multiresistant bacteria. Though the causes of multiresistance are complex, it seems the misuse of antibiotics in human medicine and more conspicuously in animal medicine and husbandry is one of the primary causes. To complicate things further, the spread of multiresistance is a pressing issue, as poor hygiene, unsafe sexual relationships, and poor food preservation are key factors that help to magnify the problem (World Health Organization 2019). Biocides and other antimicrobials could co‐select for bacteria resistant to clinically relevant antibiotics, and therefore the use of these chemicals must be revisited (Oniciuc et al. 2019).

There is collateral damage in the use of antibiotics. The large amount of antibiotics produced every year (c. 100 K tons) has environmental implications of great concern. Antibiotics are now ubiquitous in the environment. For example, they have been detected in freshwater and in fish at sublethal concentrations that can contribute to spreading bacterial resistance and changing the composition of single‐celled communities (Danner et al. 2019). The way antibiotic resistance is acquired is still under debate, but it is certainly multifactorial and complex.

Some of today's problems with antibiotic resistance are clearly growing so much and so rapidly that they seem intractable. Therefore, now more than ever, a holistic view of the problem is necessary. This book is intended to fill this gap. The first part of the book addresses the mechanisms of action of the antibiotics most used nowadays, namely, aminoglycosides, quinolones, beta‐lactams, glycopeptides, and macrolides. The mechanisms by which bacteria develop antibiotic resistance, including mutations and gene transfer, are also explained. As an issue that negatively affects the living conditions of many people, the socioeconomic impact of antibiotic resistance on public health is also discussed, with special emphasis in public policies aimed at reducing or eliminating pathogens in the environment. Special attention is given to strategies devoted to overcoming antibiotic resistance, with focus on (i) new strategies to design drugs, (ii) antibiotics from natural sources, (iii) strategies based on antimicrobials and bacteriophages, (iv) sensitizing agents to restore antibiotic activity, (v) nontraditional medicines, and (vi) therapeutic options to treat infections caused by pathogenic biofilms.

We believe this book offers a unique global perspective of the problem of antibiotic resistance, as it integrates current knowledge in all related areas from new antibiotics to the reuse of old ones, from new strategies to fight bacteria based on natural products or bacteriophages to new synthetic drugs, and from the strategies to prevent the spread of antibiotic resistance to public policies to reduce the impact of the problem.

We are in debt to everyone involved in bringing this project to fruition, especially to Professor Ramaiah who kindly proposed the idea of the book and to the Wiley Editorial Team who generously embraced the idea. We thank all the authors who generously gave their time and expertise and Gonçalo Martins for helping us to compile the contributions.

Gilberto Igrejas
José‐Luis Capelo‐Martínez

Associate Professor
University of Tras‐os‐Montes and Alto Douro

Associate Professor
NOVA University Lisbon

References

Danner, M.‐C., Robertson, A., Behrends, V., and Reiss, J. (2019). Antibiotic pollution in surface fresh waters: occurrence and effects (review). Sci. Total Environ. 664: 793–804.
Oniciuc, E.‐A., Likotrafiti, E., Alvarez‐Molina, A. et al. (2019). Food processing as a risk factor for antimicrobial resistance spread along the food chain (review). Curr. Opin. Food Sci. 30: 21–26.
WHO (2019). Antimicrobial resistance. https://www.who.int/news‐room/fact‐sheets/detail/antibiotic‐resistance (accessed 26 February 2019).

About the Editors

José‐Luis Capelo‐Martínez obtained his PhD in Analytical Chemistry from the University of Vigo in 2002 with Prof. Carlos Bendicho and his postdoc in IST in Lisbon with Prof. Ana Mota (2002–2005). He was appointed as researcher at REQUIMTE (FCT/UNL, 2005–2009) and returned to the University of Vigo to become a principal investigator for the Isidro Parga Pondal program and a researcher–lecturer (2009–2012). He was an assistant professor in FCT/UNL (2012–2018), and in 2018 he was appointed associate professor in the Department of Chemistry of the Faculty of Science and Technology in the same institution. In 2007 he obtained his Spanish habilitation in analytical chemistry and in 2017 the Portuguese habilitation in biochemistry (analytical proteomics). Dr. Capelo is a fellow of the Royal Society of Chemistry and member of the Portuguese Chemistry Society. He co‐leads the BIOSCOPE Research Group (www.bioscopegroup.org). He is the co‐CEO of the PROTEOMASS Scientific Society and founder/co‐CEO of the Chemicals start‐up Nan@rts. Dr. Capelo has been researching on the following topics: (i) quantification of metal and metal species in environmental and food samples, (ii) new methods to speed protein identification using mass spectrometry‐based workflows, (iii) accurate bottom‐up protein quantification, (iv) bacterial identification through mass spectrometry, (v) fast determination of steroids in human samples, (v) biomarker discovery, (vi) application of sensors and chemosensor to the detection/quantification of metals, and (vii) nanoproteomics and nanomedicine.

He is an author or co‐author of more than 200 manuscripts, 2 patents, 12 book chapters, and 4 books. He has mentored 12 PhD theses and currently he is mentoring 6.

Gilberto Igrejas is a professor at the University of Trás‐os‐Montes and Alto Douro (UTAD). He completed his PhD in Genetics and Biotechnology at the University of Trás‐os‐Montes and Alto Douro in collaboration with the Institut National de la Recherche Agronomique (INRA) in 2001 and a post‐graduate degree in legal medicine at the National Institute of Legal Medicine – Porto/Faculty of Medicine of Porto University in 2002. He had a postdoctoral training in molecular genetics, as Visiting Scientist, at Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia in 2004–2005. Currently he is the head of the Functional Genomics and Proteomics Unit and an integrated member of the (Bio)Chem & OMICS, LAQV/REQUIMTE of Nova University in Lisbon. His research is focused on the use of omics tools, particularly genomics and proteomics, at the molecular genetics and biotechnology level of various plant, animal, and microbial species. These are in the chronological involvement as priority research areas, based on these tools and their scope: (i) characterization of genetic resources of wheat, rye, and triticale; (ii) proteomics applied to the detection of genes responsible for the functionality and allergenicity of wheat grain, rye, and triticale; (iii) genomics and proteomics applied to antibiotic resistance; (iv) nutrigenomics and proteomics applied to the evaluation of protein species; and, finally, (v) probiotics in biotechnology and health. With regard to scientific production, he has published more than 150 articles, 12 book chapters, 20 oral presentations by invitation, 40 oral presentations, 20 articles in technical and scientific journals, and 10 educational series as well as 250 communications in scientific meetings and records in GenBank, UniProt, and MLST. Dr. Igrejas continues to work on research projects, teaches international courses for doctoral and master's degrees, and collaborates with several national and international groups. He currently supervises three postdoctoral researchers, four PhD students, seven master students, and four undergraduate students. He successfully mentored more than 120 students and participated as member of 150 academic degree evaluation panels.

Antibiotic Drug Resistance

List of Contributors

Preface

References

About the Editors

Part I
Current Antibiotics and Their Mechanism of Action