Antimicrobial Resistance: Underlying Mechanisms and Therapeutic Approaches

Preface
Contents
About the Editors
1: Antimicrobial Resistance Traits and Resistance Mechanisms in Bacterial Pathogens
	1.1 Introduction
	1.2 Antibiotics for the Treatment of Infections Caused by ESKAPE Pathogens
	1.3 Origin and Evolution of Antimicrobial Resistance Traits in ESKAPE Pathogens.
	1.4 Genomic Insights into Antimicrobial-Resistant ESKAPE Pathogens
		1.4.1 Gram-Positive ESKAPE (GP-ESKAPE) Pathogens
			1.4.1.1 Vancomycin-Resistant Enterococcus
			1.4.1.2 Staphylococcus aureus
		1.4.2 Gram-Negative ESKAPE (GN-ESKAPE) Pathogens
			1.4.2.1 Klebsiella pneumoniae
			1.4.2.2 Acinetobacter baumannii
			1.4.2.3 Pseudomonas aeruginosa
			1.4.2.4 Enterobacter Species
	1.5 Ecology of Antimicrobial Resistance Genes in ESKAPE Pathogens
		1.5.1 Plasmids
		1.5.2 Bacteriophages
		1.5.3 Transposons
		1.5.4 Integrative and Conjugative Elements (ICEs)
		1.5.5 Integrons
	1.6 Resistance Mechanisms of ESKAPE Pathogens
		1.6.1 Resistance Due to Decreased Permeability or Active Ejection of Antibiotics
		1.6.2 Resistance Due to Inactivation of the Antibiotics
			1.6.2.1 Inactivation of Antibiotics by Hydrolysis.
			1.6.2.2 Inactivation of Antibiotics by Chemical Modifications.
		1.6.3 Resistance due to Alteration of the Target Site of the Antibiotic
			1.6.3.1 Mutations of the Target Site
			1.6.3.2 Enzymatic Modification of the Target Site
			1.6.3.3 Target Protection
			1.6.3.4 Substitution or Bypassing of the Target Site
	1.7 Conclusion
	References
2: Bacterial Multidrug Tolerance and Persisters: Understanding the Mechanisms, Clinical Implications, and Treatment Strategies
	2.1 Introduction: Bacterial Multidrug Tolerance and Persister Formation
	2.2 Similarity and Difference Between Persisters and Resistant Mutants
		Box 2.1
	2.3 Different Mechanisms of Persister Formation
		2.3.1 Nonspecific Determinants
		2.3.2 Specific Determinants
	2.4 Regrowth of Persisters
	2.5 Persisters as Predecessors of Resistant Mutants
	2.6 Different Techniques to Study Bacterial Persisters
		2.6.1 Time-Kill Curves
		2.6.2 Single-Cell-Level Studies
		2.6.3 Population-Level Studies.
		2.6.4 In Vivo Models and their Relevance
		2.6.5 Future Perspectives of in Vivo Techniques
	2.7 Persister Formation in Gram-Negative Bacteria
	2.8 Persister Formation in Gram-Positive Bacteria
	2.9 Persister Formation in Mycobacteria
	2.10 Anti-Persister Strategies
		2.10.1 Inhibiting Formation of Persisters
		2.10.2 Direct Killing of Persister Cells
			2.10.2.1 Target Independent
			2.10.2.2 Target Dependent
			2.10.2.3 Repurposing of Drugs.
			2.10.2.4 Novel Approaches
	2.11 Conclusion and Perspectives
	References
3: Microbial Pathogenesis: Mechanism and Recent Updates on Microbial Diversity of Pathogens
	3.1 Diversity of Microorganisms
	3.2 Bacteria
		3.2.1 Bacterial Pathogenesis
		3.2.2 Diseases Caused by Pathogenic Bacteria in Humans
			3.2.2.1 Enterococcus faecalis
			3.2.2.2 Enterococcus faecium
			3.2.2.3 Escherichia coli
			3.2.2.4 Pseudomonas aeruginosa
			3.2.2.5 Staphylococcus aureus
			3.2.2.6 Clostridioides difficile
			3.2.2.7 Streptococcus pneumoniae
			3.2.2.8 Acinetobacter baumannii
			3.2.2.9 Klebsiella pneumoniae
			3.2.2.10 Neisseria gonorrhoeae
			3.2.2.11 Mycobacterium tuberculosis
			3.2.2.12 Helicobacter pylori
			3.2.2.13 Campylobacter spp.
			3.2.2.14 Salmonella
			3.2.2.15 Haemophilus influenzae
			3.2.2.16 Shigella spp.
	3.3 Archaea
		3.3.1 Classification of Archaea
		3.3.2 Pathogenicity in Archaea
		3.3.3 Pathogenic Archaea
	3.4 Fungi
		3.4.1 Fungal Classification
		3.4.2 Mechanism of Fungal Pathogenesis
		3.4.3 Diseases Caused by Pathogenic Fungi in Humans
			3.4.3.1 Adiaspiromycosis
			3.4.3.2 Aspergillosis
			3.4.3.3 Candidiasis
			3.4.3.4 Entomophthoromycosis
			3.4.3.5 Fungal Keratitis
			3.4.3.6 Lobomycosis
			3.4.3.7 Pneumocystis Pneumonia
			3.4.3.8 Pythiosis
			3.4.3.9 Tinea Capitis
	3.5 Protozoa
		3.5.1 Various Classes of Protozoa
		3.5.2 Pathogenesis of Protozoa
		3.5.3 Current Scenario of Pathogenic Protozoa
			3.5.3.1 Cryptosporidium Species
			3.5.3.2 Giardia intestinalis
			3.5.3.3 Entamoeba Species
			3.5.3.4 Balantidium coli
	3.6 Algae
		3.6.1 Algal Classification
		3.6.2 Microscopic Algae as Pathogens: Mechanism of Pathogenicity
		3.6.3 Disease-Causing Algae
	3.7 Virus
		3.7.1 Classification of Virus
		3.7.2 Mechanism of Pathogenesis of Viruses
		3.7.3 Deadliest Diseases Caused by Various Strains of Virus in Humans
	References
4: Pseudomonas aeruginosa: Pathogenic Adapter Bacteria
	4.1 Introduction
	4.2 Disease: An Introduction
	4.3 P. aeruginosa.
		4.3.1 History
		4.3.2 Classification
		4.3.3 Morphology
	4.4 Identification of P. aeruginosa
		4.4.1 Biochemical Test and Molecular Identification
		4.4.2 Genetics and Molecular Biology
	4.5 Pathogenicity, Morbidity, and Mortality of P. aeruginosa
	4.6 Prevention
	4.7 Treatment Option
		4.7.1 Antibiotic Option
		4.7.2 Combination Coverage
	4.8 Drug Resistance
		4.8.1 Porins
		4.8.2 Efflux
		4.8.3 Biofilm
		4.8.4 Metallo-β-Lactamases
		4.8.5 Quorum Sensing
	4.9 Summary
	References
5: Impact of Antibiotic Resistance of Bacteria in Biofilms and Microbial Fuel Cell: Confronting the Dark Box for Global Health...
	5.1 Introduction
		5.1.1 Antibiotic Resistance
		5.1.2 Antibiotics as an Organic Pollutant in Wastewater
		5.1.3 Biofilm and Antibiotics
	5.2 Molecular Mechanism of Antibiotic Resistance
	5.3 Biofilm Resistance and Tolerance
	5.4 Bio-Electrochemical Concepts in Wastewater (Microbial Fuel Cell)
	5.5 Potential for New Therapies
	5.6 Antibiotic Removal Mechanisms Based on Microbial Fuel Cell
	5.7 Overall Performance/Discussion of Antibiotic Resistance in Biofilm and Fuel Cells
	5.8 Conclusions
	References
6: Plant Secondary Metabolites for Tackling Antimicrobial Resistance: A Pharmacological Perspective
	6.1 Introduction
	6.2 Groups of Antimicrobial Plant Secondary Metabolite
		6.2.1 Phenolics
		6.2.2 Alkaloids
		6.2.3 Saponins
		6.2.4 Terpenes
		6.2.5 Flavonoids
	6.3 Mechanisms/Mode of Action of Plant Secondary Metabolites
		6.3.1 Disruption of Plasma Membrane
		6.3.2 Inhibition of DNA Replication
		6.3.3 Interference of Quorum Sensing
		6.3.4 Inhibition of Protein Synthesis
		6.3.5 Combinatorial Effect
	6.4 Mechanisms of Antimicrobial Resistance
	6.5 Pharmacological Significance of Plant Secondary Metabolites in Medicine
	6.6 Future Perspectives and Concluding Remarks
	References
7: Can Nanoparticles Help in the Battle against Drug-Resistant Bacterial Infections in ``Post-Antibiotic Era´´?
	7.1 Introduction
	7.2 Antibacterial Activity of Nanoparticles
	7.3 In Biofilm Prevention and Disruption
	7.4 Quorum Sensing Inhibitors
	7.5 Role on Efflux Pumps
	7.6 Action on Plasmids
	7.7 As delivery Systems to Combat Infections
	7.8 Nanoparticles in Detection and Diagnosis of Infection
	7.9 Other Contributions of Nanoparticles to Mitigate Drug Resistance
	7.10 Have Bacteria Developed Resistance to Nanoparticles?
	7.11 Every Rose Has Its Thorn: NPs Worsen AMR Condition
	7.12 Conclusion
	References
8: Precise Sequence-Specific Antimicrobials Based on CRISPR: Toward Prevailing Over Bacterial Antibiotic Resistance
	8.1 Introduction
	8.2 Problem(s) Associated with Conventional Antibiotics
	8.3 CRISPR/Cas Potential to Serve as Programmable Sequence-Specific Antimicrobials
	8.4 Benefits and Advantages of CRISPR-Based Antimicrobials
	8.5 Different Types of Available Nucleases for CRISPR Antimicrobials
	8.6 CRISPR Antimicrobial Delivery Systems for Targeted Killing or Antibiotic Sensitivity
	8.7 Existing Challenges for Sufficient Antimicrobial Activity and Ways of Efficacy Enhancement
		8.7.1 Resistance Against CRISPR/Cas Antimicrobials
		8.7.2 CRISPR/Cas Common Delivery Vehicles and Associated Challenges
		8.7.3 Social Issues of Using CRISPR Antimicrobials
	8.8 In Vivo Application of CRISPR Antimicrobials
	8.9 Future Prospects
	References
9: Antibiotic-Resistant Klebsiella pneumoniae and Targeted Therapy
	9.1 Introduction
	9.2 Drug Resistance in K. pneumoniae
	9.3 Mechanisms of Drug Resistance
		9.3.1 Drug Resistance Due to Efflux Pumps
		9.3.2 Drug Resistance Due to Porin Loss
		9.3.3 Drug Resistance Due to Target Modification
		9.3.4 Drug Resistance Due to Alteration of the Drug
		9.3.5 Drug Resistance Due to Biofilm Formation
	9.4 Novel Therapies to Overcome Drug Resistance in K. pneumoniae Infections
		9.4.1 Phage Therapy
		9.4.2 Nanoantibiotics
		9.4.3 Phytotherapy
		9.4.4 Combination Therapy
		9.4.5 Antimicrobial Peptides
		9.4.6 Photodynamic Therapy
	9.5 Conclusion
	References
10: Plant-Associated Endophytic Fungi and Its Secondary Metabolites Against Drug-Resistant Pathogenic Microbes
	10.1 Introduction
		10.1.1 Factors Causing the Resistance in Pathogenic Microbes
		10.1.2 Mechanism of Antibiotic Resistance
		10.1.3 Endophytes as a Source of Therapeutic Compounds
	10.2 Fungal Endophytes Against MRSA
		10.2.1 Mechanism of Resistance in S. aureus
	10.3 Fungal Endophytes Against Drug-Resistant Plasmodium Sp.
	10.4 Fungal Endophytes Against Resistant Mycobacterium Sp.
	10.5 Fungal Endophytes Against Resistant Candida albicans
	10.6 Miscellaneous
	10.7 Discussion and Conclusion
	References
11: Antimicrobial Peptides as Effective Agents Against Drug-Resistant Pathogens
	11.1 Introduction
		11.1.1 Natural Products as Prospective Source to Counter Antimicrobial Resistance
		11.1.2 Antimicrobial Drugs: History and Developments
	11.2 Antimicrobial Peptides: The Peptide-Based Drugs as Novel Class of Therapeutics to Tackle Antibiotic Resistance
		11.2.1 Identification and Properties
		11.2.2 Classification and Structure of AMPs
		11.2.3 Antimicrobial Peptides and Their Mechanism of Action
		11.2.4 AMPs in Clinical Trials as Antimicrobial Therapeutics
	11.3 Recent Progress in the Development of Peptide-Based Drugs
		11.3.1 Plant-Based Expression System for the Production of AMPs
			11.3.1.1 Plant Tissue Culture-Based Expression Systems
			11.3.1.2 Genetically Engineered Plant Systems
			11.3.1.3 Strategies for Transient Expression
			11.3.1.4 Cell Pack Method
	11.4 Computational Biology-Based Antimicrobial Research
	11.5 Challenges Associated with Development of AMPs as Antimicrobial Therapeutics
	11.6 Commercial Success and Prospects of AMPs as Antimicrobial Therapeutics
	References
12: Essential Oils for Combating Antimicrobial Resistance: Mechanism Insights and Clinical Uses
	12.1 Introduction
	12.2 Antibacterial Effects of Essential Oils
	12.3 Antibacterial Mechanisms of EOs and Their Bioactive Compounds Against Bacteria
		12.3.1 Antibacterial Mechanisms of EOs
		12.3.2 Antibacterial Mechanisms of Volatile Bioactive Compounds
	12.4 Clinical Investigation of Bioactive Compounds from Essential Oils Against Bacteria
	12.5 Conclusions and Perspectives
	References
13: Antimicrobial Resistance and Medicinal Plant Products as Potential Alternatives to Antibiotics in Animal Husbandry
	13.1 Introduction
	13.2 Antibiotic Use in Animal Husbandry
	13.3 Antimicrobial Resistance in Animal Husbandry
	13.4 Medicinal Plant Resources as Classes of Alternatives
		13.4.1 Probiotics
		13.4.2 Prebiotics
		13.4.3 Synbiotics
		13.4.4 Enzymes
		13.4.5 Phytogenics
		13.4.6 Essential Oils
		13.4.7 Phytochemicals
		13.4.8 Antimicrobial Peptides
	13.5 Medicinal Plant Products Targeting Pathogenicity
		13.5.1 Quorum Sensing Inhibitors
		13.5.2 Efflux Pump Inhibitors
		13.5.3 Bacterial Virulence Inhibitor
		13.5.4 Biofilm Inhibitors
	References
14: Recent Updates on Bacterial Secondary Metabolites to Overcome Antibiotic Resistance in Gram-Negative Superbugs: Encouragem...
	14.1 Introduction
		14.1.1 Antibiotic Resistance: A Perfect Storm
		14.1.2 Socioeconomic Impact of Antibiotic Resistance
	14.2 The Need for New Antibiotics
		14.2.1 The Golden Era of Antibiotics Versus the ``Void´´ in the Discovery Pipeline
	14.3 Can We Rely Upon Bacterial Hidden Treasure to Find New Antibiotics?
		14.3.1 Natural Products Versus Synthetic Compounds
		14.3.2 Untapped Bacterial Diversity as a Source of New and Effective Antibiotics
			14.3.2.1 Novel Tetracyclines
			14.3.2.2 Cefiderocol
			14.3.2.3 Bacteriocins
				Enterocin E 760
			14.3.2.4 Bacteriocin E 50-52 and B 602
			14.3.2.5 Macrolactin S
			14.3.2.6 Pulvomycin
			14.3.2.7 Plazomicin
			14.3.2.8 Novel Polymyxin Derivatives
			14.3.2.9 Octapeptins
			14.3.2.10 Paenibacterin
			14.3.2.11 Cystobactamids
			14.3.2.12 Paenipeptins
			14.3.2.13 Brevicidine and Laterocidin
			14.3.2.14 Odilorhabdins
			14.3.2.15 Optimized Arylomycins
			14.3.2.16 Tridecaptins
			14.3.2.17 Darobactin
			14.3.2.18 Picolinamycin
	14.4 Bacteria as a Potential Source of Antibiotic Adjuvants/Resistance-Modifying Agents (RMAs)
		14.4.1 beta-Lactamase Inhibitors (BLI)
		14.4.2 Efflux Pump Inhibitors (EPIs)
		14.4.3 Quorum Sensing Inhibitors (QSIs)
		14.4.4 Biofilm Inhibitors
		14.4.5 Outer Membrane Permeabilizers
	14.5 Concluding Remarks
	References
15: Plant Essential Oils for Combating Antimicrobial Resistance via Re-potentiating the Fading Antibiotic Arsenal
	15.1 Introduction
	15.2 Methodology
	15.3 Possible Mechanism of Action of Essential Oil from Plants in Drug-Resistant Microbes
		15.3.1 Mode of Action of Essential Oils in Bacteria
			15.3.1.1 Altered Membrane Permeability of Bacterial Cell
			15.3.1.2 Bacterial Efflux Pump Inhibition
			15.3.1.3 Essential Oil as a Beta-Lactamase Inhibitor
			15.3.1.4 Anti-quorum Sensing
		15.3.2 Mode of Action of Essential Oils in Fungus
			15.3.2.1 Cell Membrane Disruption, Alteration, and Inhibition of Cell Wall Formation
			15.3.2.2 Dysfunction of the Fungal Mitochondria
			15.3.2.3 Inhibition of Efflux Pump in Fungal Cell Membrane
		15.3.3 Mode of Action of Essential Oils in Protozoa
		15.3.4 Mode of Action of Essential Oils in Viruses
	15.4 Plant-Based Essential Oil Chemistry and Family-Wise Description of In Vitro Antimicrobial Activity of Essential Oil Again...
		15.4.1 Annonaceae
		15.4.2 Apiaceae
		15.4.3 Aristolochiaceae
		15.4.4 Asteraceae
		15.4.5 Brassicaceae
		15.4.6 Lauraceae
		15.4.7 Lamiaceae
		15.4.8 Moraceae
		15.4.9 Myrtaceae
		15.4.10 Oleaceae
		15.4.11 Poaceae
		15.4.12 Rutaceae
		15.4.13 Santalaceae
		15.4.14 Schisandraceae
		15.4.15 Verbenaceae
		15.4.16 Umbelliferae
		15.4.17 Zingiberaceae
	15.5 Synergistic Formulations by Combination of Antimicrobials and Essential Oils to Reverse Resistance
	15.6 Concluding Remarks
	References
16: Bacterial Drug Efflux Pump Inhibitors from Plants
	16.1 Introduction
	16.2 Bacterial Efflux Pump Systems: An Overview
		16.2.1 Background
		16.2.2 Classification and Physiology of Efflux Pump Systems
			16.2.2.1 Families of Drug Efflux Pumps
			16.2.2.2 Structure of Drug Efflux Pumps
			16.2.2.3 Energy Sources of Drug Efflux Pumps
			16.2.2.4 Substrate Recognition
			16.2.2.5 Mechanisms of Drug Efflux
			16.2.2.6 Specificities of Efflux Pump Families
				ATP-Binding Cassette (ABC) Superfamily
				Major Facilitator Superfamily (MFS)
				Small Multidrug Resistance (SMR) Family
				Multidrug and Toxic Extrusion (MATE) Family
				Resistance-Nodulation-Cell Division (RND) Superfamily
		16.2.3 Public Health Significance of Multidrug Efflux Pumps
	16.3 Efflux Pump Inhibitors (EPIs)
		16.3.1 EPIs as Promising Therapeutic Agents to Reverse Bacterial MDR
		16.3.2 Properties of an Effective Efflux Pump Inhibitor
		16.3.3 Classification of Efflux Pump Inhibitors
			16.3.3.1 Classes of Efflux Pump Inhibitors Based on their Mechanisms of Action
				Energy Dissipation
				Direct Binding Inhibition
			16.3.3.2 Classes of EPIs Based on their Origin
				EPIs Originated from Plants
				EPIs Originated from Microorganisms
				EPIs Originated from Chemical Synthesis
	16.4 Methods of Screening Efflux Pump Inhibitors
		16.4.1 Direct Measurement of Efflux Activity
		16.4.2 Accumulation Assay
	16.5 Efflux Pump Inhibitors (EPIs) from Plants
		16.5.1 Terpenoids
		16.5.2 Phenolic Compounds
		16.5.3 Alkaloids
	16.6 Drugs from Plant-Derived EPIs: Current Stage and Challenges in Drug Development and Clinical Use
		16.6.1 Current Stage of Development of Plant-Derived EPI Drugs
		16.6.2 Current Challenges in the Development and Clinical Use of Plant-Derived EPI Drugs
	16.7 Future Perspectives
	16.8 Conclusion
	References
17: Anti-Quorum Sensing Agents from Natural Sources
	17.1 Introduction
	17.2 Overview on Quorum Sensing
		17.2.1 Quorum Sensing in Gram-Positive Bacteria
		17.2.2 Quorum Sensing in Gram-Negative Bacteria
	17.3 Quorum Quenching of Bioactive Compounds from Medicinal Plants
		17.3.1 Quorum Quenching of Terpenes
		17.3.2 Quorum Quenching of Flavonoids
		17.3.3 Quorum Quenching of Phenolic Acids
	17.4 Conclusion
	References
18: Plant-Assisted Plasmid Curing Strategies for Reversal of Antibiotic Resistance
	18.1 Introduction
	18.2 Why Target Plasmids?
	18.3 Strategies for Removing MGEs
		18.3.1 Elimination of Plasmid
		18.3.2 Inhibition of Conjugation
	18.4 Biological Strategies for Elimination of MGEs
	18.5 Nanoparticles in Plasmid Curing
	18.6 CRISPR-Cas9-Based Approach to Plasmid Curing
	18.7 Stress-Free Strategy to Cure Plasmid
	18.8 Rationale for the Use of Plant Resources in Drug Resistance Reversal
	18.9 Plant-Derived Plasmid Curing Agents
	18.10 Plant Extracts in Plasmid Curing/Conjugal Inhibition
	18.11 Plant-Assisted Nanoparticles as Plasmid Curing Agents
	18.12 Future of Plant-Assisted Curing Agents
	References
19: Natural Product as Efflux Pump Inhibitors Against MRSA Efflux Pumps: An Update
	19.1 Introduction
	19.2 Screening of Efflux Pump Inhibitors
		19.2.1 Accumulation Assay (EtBr or Berberine)
		19.2.2 Susceptibility Testing
		19.2.3 MIC Synergy Testing in the Presence of EPI
		19.2.4 Fractional Inhibitory Testing (FIC)
		19.2.5 Time Kill Studies
		19.2.6 Natural Product Inhibitors of Efflux Pumps
			19.2.6.1 S.aureus NorA Multidrug Efflux Pump Inhibitors
		19.2.7 Polyphenols
			19.2.7.1 2-Arylbenzofuran
			19.2.7.2 N-Caffeoylphenylkylamides
			19.2.7.3 Caffeoylquinic Acids
			19.2.7.4 Terpenoids
			19.2.7.5 Oligosaccharides
			19.2.7.6 Alkaloids
			19.2.7.7 Miscellaneous NorA EPIs
			19.2.7.8 MsrA Efflux Pump Inhibitors of Natural Product Origin
			19.2.7.9 Miscellaneous S. aureus and MRSA Efflux Pump Inhibitors of Natural Product Origin
	19.3 Concluding Remarks
	References