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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

Part I Current Antibiotics and Their Mechanism of Action
1 Resistance to Aminoglycosides: Glycomics and the Link to the Human Gut Microbiome
1.1 Aminoglycosides as Antimicrobial Drugs
1.1.1 The Structure of Aminoglycosides
1.1.2 Mechanisms of Action
1.2 Mechanisms of Resistance
1.2.1 Aminoglycoside-Modifying Enzymes
1.2.2 Mutation or Modification of Ribosomal Target Sequences
1.2.3 Changes in Uptake and Efflux
1.3 Development of New AGAs: The Potential of Glycomics
1.3.1 Exploitation of Carbohydrate Chemistry to Study Structure-Activity Relationship of Aminoglycoside Derivatives
1.3.2 Aminoglycoside Microarrays to Screen Interactions of Antibiotics with RNAs and Proteins
1.4 Influence of the Human Microbiome in Aminoglycoside Resistance
1.4.1 The Effect of Antibiotic-Induced Alterations
1.4.2 A Reservoir of Antibiotic Resistance
1.4.3 Strategies to Modulate the Human Microbiome
1.5 Conclusions and Outlook
2 Mechanisms of Action and of Resistance to Quinolones
2.1 Introduction
2.2 Mechanism of Action of Quinolones
2.3 Mutations in the Genes Encoding the Targets of Quinolones
2.4 Multidrug Efflux Pumps and Quinolone Resistance
2.5 Transferable Quinolone Resistance
2.6 Stenotrophomonas maltophilia and Its Uncommon Mechanisms of Resistance to Quinolones
3 Beta-Lactams
3.1 Introduction
3.2 Chemical Structure
3.3 Classification and Spectrum of Activity
3.3.1 Penicillins
3.3.2 Cephalosporins
3.3.3 Monobactams
3.3.4 Carbapenems
3.3.5 Beta-Lactam Associated with Beta-Lactamase Inhibitors
3.4 Mechanism of Action
3.5 Activity of Beta-Lactams Against Multiresistant Bacteria
3.6 Conclusions
4 Glycopeptide Antibiotics: Mechanism of Action and Recent Developments
4.1 Introduction
4.2 Naturally Occurring Glycopeptide Antibiotics
4.3 Mechanism of Action of Glycopeptide Antibiotics
4.4 Resistance to Glycopeptides
4.5 Second-Generation Glycopeptides
4.5.1 Telavancin
4.5.2 Dalbavancin
4.5.3 Oritavancin
4.6 Strategies to Overcome Resistance to Glycopeptides
4.6.1 Modifications That Enhance the Binding Affinity to Target Pentapeptide
4.6.2 Incorporation of Lipophilicity
4.6.3 Incorporation of Lipophilic Cationic Moieties to Impart Membrane Disruption Properties
4.6.4 Incorporation of Metal Chelating Moiety to Vancomycin to Impart New Mechanism of Action
4.7 Glycopeptides Under Clinical Trials
4.8 Glycopeptide Antibiotics: The Challenges
5 Current Macrolide Antibiotics and Their Mechanisms of Action
5.1 Introduction
5.2 Structure of Macrolides
5.3 Macrolide Mechanisms of Action
5.4 Clinical Use of Macrolides
5.5 Next-Generation Macrolides and Future Use
Part II Mechanism of Antibiotic Resistance
6 Impact of Key and Secondary Drug Resistance Mutations on Structure and Activity of -Lactamases
6.1 Introduction
6.2 Structure of the Protein Globule of TEM-Type -Lactamases: Catalytic and Mutated Residues
6.2.1 Catalytic Site of -Lactamase TEM-1
6.2.2 Mutations Causing Phenotypes of TEM-Type -Lactamases
6.3 Effect of the Key Mutations on Activity of TEM-Type -Lactamases
6.3.1 Single Key Mutations in TEM-Type ESBLs (2be)
6.3.2 Combinations of Key Mutations in TEM-Type ESBLs (2be)
6.3.3 Key Mutations in IRT TEM-Type -Lactamases (2br)
6.3.4 Single Key Mutations in IRT TEM-Type -Lactamases (2br)
6.3.5 Combinations of Key Mutations in IRT TEM-Type -Lactamases (2br)
6.3.6 Combinations of Key ESBL and IRT Mutations in CMT TEM-Type -Lactamases (2ber)
6.4 Effect of Secondary Mutations on the Stability of TEM-Type -Lactamases
6.5 Conclusions
7 Acquired Resistance from Gene Transfer
7.1 Introduction
7.2 Horizonal Gene Transfer: A Brief Overview
7.2.1 Transformation
7.2.2 Transduction
7.2.3 Conjugation
7.3 Conjugative Transfer Mechanisms
7.3.1 Conjugative Transfer of Plasmids
7.3.2 Conjugative Transfer of Integrative Conjugative Elements
7.3.3 Conjugative Transfer of Other Integrative Elements
7.4 Antibiotic Resistances and Their Transfer
7.4.1 Dissemination of Carbapenem Resistance Among Bacterial Pathogens
7.4.2 Dissemination of Cephalosporin Resistance Among Bacterial Pathogens
7.4.3 Dissemination of Methicillin Resistance Among Bacterial Pathogens
7.4.4 Dissemination of Vancomycin Resistance Among Bacterial Pathogens
7.4.5 Dissemination of Fluoroquinolone Resistance Among Bacterial Pathogens
7.4.6 Dissemination of Penicillin and Ampicillin Resistance Among Bacterial Pathogens
7.5 Nanotubes Involved in Acquisition of Antibiotic Resistances
7.6 Conclusions and Outlook
8 Antimicrobial Efflux Pumps
8.1 Bacterial Antimicrobial Efflux Pumps
8.1.1 Active Drug Efflux Systems
8.1.2 Secondary Active Drug Transporters
9 Bacterial Persistence in Biofilms and Antibiotics: Mechanisms Involved
9.1 Introduction
9.2 Reasons for Failure of Antibiotics in Biofilms
9.2.1 Failure of Antibiotics to Penetrate Biofilm: Active Antibiotics on the Biofilm
9.2.2 Outer Membrane Vesicles (OMVs)
9.2.3 Horizontal Transfer of Encoding -Lactamase Genes
9.2.4 Influence of Subinhibitory Concentrations of Antibiotics on Biofilm
9.2.5 Small Colony Variants (SCVs), Persistence (Persisters), and Toxin-Antitoxin (TA) Systems
9.2.6 Quorum Sensing: Bacterial Metabolites
9.2.7 Extracellular DNA
9.2.8 Nutrient Limitation
9.2.9 SOS Inducers (Antibiotics and Others)
9.2.10 Hypermutator Phenotype
9.2.11 Multidrug Efflux Pumps
9.3 Usual and Innovative Means to Overcome Biofilm Resistance in Biofilms
9.3.1 Antibiotics (Bacteriocins) Natural and Synthetic Molecules: Phages
9.3.2 Efflux Pump Inhibitors
9.3.3 Anti-Persisters: Quorum-Sensing Inhibitors
9.3.4 Enzymes
9.3.5 Electrical Methods
9.3.6 Photodynamic Therapy
9.4 Conclusion
Part III Socio-Economical Perspectives and Impact of AR
10 Sources of Antibiotic Resistance: Zoonotic, Human, Environment
10.1 The Antibiotic Era
10.2 Intrinsic and Acquired Antibiotic Resistance
10.3 The Natural Antibiotic Resistome
10.4 The Contaminant Resistome
10.5 Evolution of Antibiotics Usage
10.6 Antibiotic Resistance Evolution
10.7 Stressors for Antibiotic Resistance
10.8 Paths of Antibiotic Resistance Dissemination
10.9 Antibiotic Resistance in Humans and Animals
10.10 Final Considerations
11 Antibiotic Resistance: Immunity-Acquired Resistance: Evolution of Antimicrobial Resistance Among Extended-Spectrum -Lactamases and Carbapenemases in Klebsiella pneumonia and Escherichia coli
11.1 Overview of Antibiotic Resistance as a Worldwide Health Problem
11.2 Objectives
11.3 Causes of Antimicrobial Resistance
11.4 Enterobacteriaceae: General Characterization
11.4.1 Escherichia coli
11.4.2 Klebsiella pneumoniae
11.5 Current Antibiotic Resistance Threats
11.5.1 Carbapenem-Resistant Enterobacteriaceae
11.5.2 Extended-Spectrum -Lactamase
11.6 Consequences and Future Strategies to Brace the Antibiotic Backbone
11.7 Concluding Remarks and Future Perspectives
12 Extended-Spectrum- -Lactamase and Carbapenemase-Producing Enterobacteriaceae in Food-Producing Animals in Europe: An Impact on Public Health?
12.1 Extended-Spectrum -Lactamase
12.1.1 ESBL-Producing Enterobacteriaceae in Food Animals
12.2 Carbapenemases
5 12.3 Concluding Remarks
Part IV Therapeutic Strategy for Overcoming AR
13 AR Mechanism-Based Drug Design
13.1 Introduction
13.2 Drug Design Principles
13.3 Identification of Novel Targets and Novel Mechanisms of Action
13.4 Efflux Pump Inhibitors
13.5 Design of Inhibitors of Drug-Modifying Enzymes
13.6 Antimicrobial Peptides
13.7 Other Approaches to Overcome Bacterial Resistance
13.8 Conclusion
14 Antibiotics from Natural Sources
14.1 Introduction
14.1.1 The Origin of Microbial Resistance Gene Products
14.2 Organization of the Following Sections
14.3 Peptidic Antibiotics (Both Cyclic and Acyclic)
14.3.1 Tyrocidines, Gramacidins, and Derivatives
14.3.2 Streptogramins and Derivatives: Cyclic Peptides
14.3.3 Arylomycins (Lipopeptide and Modification
14.3.4 Daptomycin (Cyclic Depsilipopeptide)
14.3.5 Colistins (Cyclic Peptides with a Lipid Tail)
14.3.6 Glycopeptides
14.3.7 Host Defense Peptides
14.4 -Lactams: Development, Activities, and Chemistry
14.4.1 Combinations with -Lactamase Inhibitors
14.5 Aminoglycosides
14.5.1 Streptomycin
14.5.2 Plazomicin
14.6 Early Tetracyclines: Aureomycin and Terramycin
14.6.1 Semisynthetic Tetracyclines from 2005
14.7 Erythromycin Macrolides
14.7.1 Recent Semisynthetic Macrolides
14.8 Current Methods of "Discovering Novel Antibiotics"
14.8.1 Introduction
14.8.2 Initial Rate-Limiting Step (Irrespective of Methods)
14.8.3 Genomic Analyses of Whole Microbes
14.8.4 Isolated Genomics
14.8.5 New Sources (and Old Ones?) for Investigation
14.8.6 "Baiting" for Microbes
14.8.7 Use of Elicitors
14.9 Conclusions
14.9.1 Funding?
14.9.2 The "Take-Home Lesson"
15 Bacteriophage Proteins as Antimicrobials to Combat Antibiotic Resistance
15.1 Introduction
15.2 Polysaccharide Depolymerases
15.2.1 Depolymerase Structure
15.2.2 Depolymerase Classification
15.2.3 Depolymerase Activity Assessment
15.2.4 Depolymerases as Antimicrobials
15.2.5 Remarks on Depolymerases
15.3 Peptidoglycan-Degrading Enzymes
15.3.1 Virion-Associated Lysins (VALs)
15.3.2 Gram-Positive Targeting Endolysins
15.3.3 Gram-Negative Targeting Endolysins
15.4 Holins
15.4.1 Holin Structure
15.4.2 Holins as Antimicrobials
15.4.3 Remarks on Holins
15.5 Final Considerations
16 Antibiotic Modification Addressing Resistance
16.1 Chemical Synthesis of New Antibiotics
16.2 Antibiotic Modification with Targeted Groups
16.3 Antibiotic Modification with Photo-Switching Units
16.4 Antibiotic Modification by Supramolecular Chemistry
16.5 Antibiotic Modification by Complexed with Other Materials
16.6 Conclusion
17 Sensitizing Agents to Restore Antibiotic Resistance
17.1 Introduction
17.2 Sensitizing Strategies Directly Targeting Resistance Mechanisms
17.2.1 Inhibition of -Lactamases
17.2.2 Drug Efflux Pump Inhibitors (EPIs)
17.3 Sensitizing Strategies Circumventing Resistance Mechanisms
17.3.1 Manipulating Bacterial Homeostasis
17.3.2 Cell Wall/Membrane Proteins
17.3.3 Biofilms and Quorum Sensing
17.3.4 Persister Cells
17.3.5 Targeting Nonessential Genes/Proteins
17.3.6 Bacteriophages
17.4 Using and Strengthening the Human Immune System Against Resistant Bacteria
17.4.1 Strengthening Host Immune System Function
17.4.2 Antimicrobial Peptides (AMPs)
17.5 Conclusion
18 Repurposing Antibiotics to Treat Resistant Gram-Negative Pathogens
18.1 Introduction
18.2 Anti-Virulence Strategy
18.3 Antibiotic Combination Strategy
18.4 Antibiotic-Antibiotic Combination Approach
18.5 Antibiotic-Adjuvant Combination Approach
18.6 -Lactam and -Lactamase Inhibitor Combination
18.7 Imipenem-Cilastatin/Relebactam Triple Combination
18.8 Aspergillomarasmine A
18.9 Intrinsic Resistance Challenges and Strategies to Overcome Them
18.10 Repurposing of Hydrophobic Antibiotics with High Molecular Weight by Enhancing Outer Membrane Permeability Using Polybasic Adjuvants
18.11 Repurposing of Hydrophobic Antibiotics with Large Molecular Weight and Other Antibacterials as Antipseudomonal Agents Using Polybasic Adjuvants
18.12 Repurposing of Antibiotics as Potent Agents Against MDR GNB
18.13 Outlook and Conclusions
19 Nontraditional Medicines for Treatment of Antibiotic Resistance
19.1 Introduction
19.2 Antibodies
19.2.1 Raxibacumab Versus Bacillus anthracis
19.2.2 Bezlotoxumab Versus Clostridium difficile
19.2.3 Panobacumab Versus Pseudomonas aeruginosa
19.2.4 LC10 Versus Staphylococcus aureus
19.3 Immunomodulators
19.3.1 Antibodies plus Polymyxins
19.3.2 Antibodies plus Vitamin D
19.3.3 Antibodies plus Clavanin
19.3.4 Antibodies plus Reltecimod
19.4 Potentiators of Antibiotic Activity
19.4.1 Antibiotic-Antibiotic Combinations
19.4.2 Pairing of Antibiotic with Nonantibiotic
19.5 Bacteriophages
19.5.1 Life Cycles of Bacteriophages
19.5.2 Bacteriophage Therapy
19.5.3 Phage Enzymes
19.5.4 Concerns About the Application of Phage to Treat Bacteria
19.6 Therapy with Essential Oils
19.7 Microbiota-Based Therapy
19.7.1 Microbiota Modulation Probiotics Prebiotics
19.7.2 Stool Microbiota Transplant
20 Therapeutic Options for Treatment of Infections by Pathogenic Biofilms
20.1 Introduction
20.2 Antibiotic Therapy for the Treatment of Pathogenic Biofilms
20.2.1 Monotherapy
20.2.2 Antibiotic Combination Therapy
20.3 New Findings for the Treatment of Pathogenic Biofilms
20.3.1 AMPs Applied to Treatment Pathogenic Biofilms
20.3.2 Bacteriophage Therapy Anti-Biofilm
20.3.3 Nanotechnology Applied to the Treatment of Pathogenic Biofilms
20.4 Conclusion and Future Directions
Part V Strategies to Prevent the Spread of AR
21 Rapid Analytical Methods to Identify Antibiotic-Resistant Bacteria
21.1 Introduction
21.2 Standard Methods for Antibiotic Sensitivity Testing
21.3 Rapid Cultural Methods
21.4 Rapid Serological Methods
21.5 Rapid Molecular (Genetic) Methods
21.6 Mass Spectrometric Methods
21.7 Flow Cytometric Methods
21.8 Conclusions
22 Effective Methods for Disinfection and Sterilization
22.1 Introduction
22.2 Disinfection and Sterilization: Methods and Factors Involved in Their Efficacy
22.2.1 Methods of Sterilization and Disinfection
22.2.2 Factors Influencing Disinfection and Sterilization Efficacy
22.3 Resistance to Disinfectants
22.3.1 Molecular Mechanisms of Biocide Resistance
22.3.2 Biofilms
22.3.3 Cross-Resistance Between Antibiotics and Disinfectants
22.4 New Technologies as Alternatives to Classical Disinfectants
22.4.1 Chemical and Physical Disinfectants
22.4.2 Antimicrobial Surfaces
22.4.3 Biological Disinfectants
22.5 Current Legislation
22.6 Conclusions
23 Strategies to Prevent the Spread of Antibiotic Resistance: Understanding the Role of Antibiotics in Nature and Their Rational Use
23.1 Introduction
23.2 Agriculture as the Largest Consumer of Antimicrobials
23.3 Antimicrobials and Antimicrobial Resistance
23.4 First-Generation Tetracyclines: Discovery and Usage
23.5 Tetracycline Resistance Mechanisms
23.6 Phylogeny of Tetracycline Resistance Genes
23.7 Second-Generation Tetracyclines
23.8 Third-Generation Tetracyclines
23.9 Resistance to Third-Generation Tetracyclines
23.10 Other Potential Resistance Mechanisms Toward Third-Generation Tetracyclines
23.11 Evolutionary Aspect of tet(X)
23.12 Ecological Aspects of tet(X)
23.13 Antibiotics and Antibiotic Resistance as Integral Parts of Microbial Diversity
23.14 The Role of Antibiotics in Natural Ecosystems
23.15 Low-Dose Antibiotics: Phenotypic Effects
23.16 Low-Dose Antibiotics: Genetic Effects

23.17 Regulation of Antibiotic Synthesis in Antibiotic Producers
23.18 Convergent Evolution of Antibiotics as Signaling Molecules
23.19 Carbapenems: Convergent Evolution and Regulation in Different Bacteria
23.20 Antibiotics and Antibiotic Resistance: Environmental and Anthropogenic Contexts
23.21 Conclusions
Part VI Public Policy
24 Strategies to Reduce or Eliminate Resistant Pathogens in the Environment
24.1 Introduction
24.2 Sources of Resistant Bacteria in the Environment
24.3 Sewage and Wastewater
24.3.1 Sewage Treatment Plants
24.3.2 Non-Treated Sewage
24.3.3 Industrial Wastewater Effluents
24.3.4 Environmental Antibiotic Resistance is a Poverty Problem
24.4 Agriculture
24.4.1 Intensive, Large-Scale Animal Husbandry
24.4.2 Manure Application
24.4.3 Agriculture in Developing Countries
24.4.4 Aquaculture
24.5 De Novo Resistance Selection
24.6 Relevant Risk Scenarios
24.7 Management Options
24.7.1 Possible Interventions on the Level of Releases of Resistant Bacteria
24.7.2 Restricting Transmission of Resistant Bacteria from the Environment
24.7.3 Better Agriculture Practices to Sustain the Lifespans of Antibiotics
24.7.4 Limiting Selection for Resistance in the Environment
24.8 Final Remarks
John Wiley & Sons, Ltd.
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