Drug Discovery Targeting Drug-Resistant Bacteria

Chapter 1 - Antibiotics: past, present, and future
	1 - Introduction
		1.1 - History and discovery of antimicrobials
	2 - Current status
		2.1 - Dwindling drug discovery pipeline: no new class of antibiotics from the last three decades
		2.2 - Pharmaceutical companies dropped out the research and development of antibiotics
	3 - Solution to the problem: what can be done?
		3.1 - A surveillance system to monitor the escalating antimicrobial resistance
		3.2 - One Health approach
		3.3 - Introducing new chemical entities and managing current antibiotics
	References
CHAPTER 2 - Mechanisms of antibacterial drug resistance and approaches to overcome
	1. Introduction
	2. Mechanisms of antibacterial drug action
		2.1 Interference with the cell-wall synthesis
		2.2 Inhibition of protein synthesis
		2.3 Interference with nucleic acid synthesis
			2.3.1 Inhibit DNA synthesis
			2.3.2 Inhibit RNA synthesis
		2.4 Inhibition of metabolic pathways of essential metabolites such as the folic acid
		2.5 Disruption and increased permeability of cytoplasmic membrane structure
	3. Mechanisms of developing antibacterial resistance
		3.1 Modification of the antibiotic molecule
		3.2 Destruction of the antibiotic molecule
		3.3 Decreased antibiotic penetration and efflux
			3.3.1 Decreased permeability
			3.3.2 Efflux pumps
		3.4 Changes in target sites
			3.4.1 Target protection
			3.4.2 Modification of the target site
				3.4.2.1 Mutations lead to alteration of the target site
				3.4.2.2 Alteration of the target site by enzymes
				3.4.2.3 Change or bypass of the target site
		3.5 Resistance by global cell adaptations
	4. Mechanisms of the spread of antibacterial resistance
		4.1 Genetic basis and mechanisms of spreading antibacterial resistance
		4.2 Emergence of antibacterial resistance
	5. The most harmful multidrug-resistant strains
	6. New antibacterial drug targets and novel approaches to drug development
	7. Conclusion
	Acknowledgments
	References
Chapter 3 - Antibiotics targeting Gram-negative bacteria
	1 - Gram-negative infections: the unmet need
		1.1 - Mechanisms of resistance and their epidemiology
			1.1.1 - Resistance to carbapenems
			1.1.2 - Resistance to polymyxins
	2 - Combating multidrug resistance with new drugs
		2.1 - Compounds with novel targets
		2.2 - Combinations of approved antibiotics with partners that enhance the activity of the antibiotic
			2.2.1 - SPR741 combination
			2.2.2 - β-Lactam and β-lactamase inhibitors
			2.2.3 - Imipenem/cilastin + relebactam
			2.2.4 - Sulbactam + ETX2514
			2.2.5 - Meropenem + nacubactam
			2.2.6 - Cefepime + zidebactam (WCK-5222)
			2.2.7 - ETX0282 cefpodoxime proxetil
			2.2.8 - Cefepime + VNRX-5133
			2.2.9 - Cefepime + AAI101
		2.3 - Analogs of existing classes of antibiotics (cefiderocol, tetracycline, aminoglycoside, and polymyxin)
			2.3.1 - Compounds in clinical development
	3 - What the future holds
	References
Chapter 4 - Recent development of antibacterial agents to combat drug-resistant Gram-positive bacteria
	1 - Introduction
	2 - Antibacterial drugs under clinical development
	3 - Nature-derived antibiotics
		3.1 - Antibiotics discovered from the soil microbiome
			3.1.1 - Teixobactin
			3.1.2 - Malacidins
			3.1.3 - Lysocins
		3.2 - Antibiotics discovered from human microbiome
	4 - Semisynthetic antibiotics
		4.1 - Semisynthetic β-lactams
		4.2 - Semisynthetic tetracyclines
		4.3 - Semisynthetic macrolides
		4.4 - Semisynthetic glycopeptides
	5 - Synthetic antibacterial agents
		5.1 - Synthetic antibacterial agents derived from screening process
			5.1.1 - Retinoids
			5.1.2 - Oxadiazoles
		5.2 - Synthetic antibacterial agents inspired from antibacterial peptides
			5.2.1 - Small molecular antibacterial peptide mimics
			5.2.2 - Macromolecular antibacterial peptide mimics
	6 - Conclusion and future prospects
	References
Chapter 5 - Repurposing nonantibiotic drugs as antibacterials
	1 - Introduction
	2 - Ibuprofen
	3 - Ethyl bromopyruvate
	4 - Disulfiram
	5 - Diphenyleneiodonium chloride
	6 - Ivacaftor
	7 - Ebselen
	8 - Niclosamide
	9 - Loperamide
	10 - Antidepressants
	11 - Sertraline
	12 - Amitriptyline
	13 - Anti-virulence agents
	14 - Pentetic acid
	15 - Diflunisal
	16 - Metformin
	17 - Auranofin
	18 - Floxuridine
	19 - Gemcitabine
	20 - Streptozotocin
	21 - Statins
	22 - Nicotinamide
	23 - Dexamethasone
	24 - Celecoxib
	25 - Pentamidine
	26 - Zidovudine
	27 - Ciclopirox
	28 - Gallium compounds
	29 - 5-Fluorouracil
	30 - Conclusion
	Acknowledgments
	References
	Further readings
Chapter 6 - Drugs against Mycobacterium tuberculosis
	List of abbreviations
	1 - Introduction
	2 - Tuberculosis drug discovery and development of treatment regimens
	3 - Intrinsic and acquired drug resistance in Mycobacterium tuberculosis
		3.1 - Mechanisms of resistance against first-line drugs
		3.2 - Mechanism of resistance against second-line drugs
	4 - Drug susceptibility testing and its importance
	5 - Drugs currently under development for tuberculosis
	6 - Host-directed therapies for treating tuberculosis
	7 - Conclusion
	References
Chapter 7 - Combating biothreat pathogens: ongoing efforts for countermeasure development and unique challenges
	Abbreviations
	1 - Introduction
	2 - Biothreat agents
		2.1 - Bacterial biothreat agents
		2.2 - Viral biothreat agents
	3 - Screening strategies to identify therapeutics against biothreat agents
		3.1 - High-throughput screening approaches to identify therapeutics against bacterial agents
		3.2 - Screening platforms for biothreat viral agents
		3.3 - Identification of host factors required for pathogen replication through knowledge-based or multiomics screening
	4 - Development of countermeasures to biothreat agents
		4.1 - Host-directed therapy
		4.2 - Antibody therapy
		4.3 - Antiviral medical countermeasures
		4.4 - Combination therapies
	5 - Unique preclinical challenges
	6 - Clinical trials and the animal rule
	7 - Summary and conclusion
	References
Chapter 8 - New approaches to antibacterial drug discovery
	1 - Introduction
	2 - Natural products and drug discovery
		2.1 - Innovative drug discovery methods from natural products
		2.2 - Natural products diversification for drug discovery
			2.2.1 - Chemical investigation of unexplored natural sources
				2.2.1.1 - Activation of biosynthetic gene clusters
				2.2.1.2 - Light-driven structure diversification
			2.2.2 - Biological approaches
			2.2.3 - Synthetic chemistry approaches
	3 - Target-based drug discovery
		3.1 - Peptide-based drug discovery: reverse pharmacology approach and phage display libraries
		3.2 - Antibody-based drug discovery
		3.3 - Fragment-based drug discovery
	4 - Quorum sensing and drug discovery
		4.1 - Quorum sensing inhibition mechanisms
		4.2 - The antipathogenic effect of quorum sensing inhibitors
	5 - Automation in molecule design
		5.1 - Automated de novo design
		5.2 - Molecular docking
		5.3 - Microfluids-based synthesis
	6 - Biosensors role in drug discovery
	7 - Stem cells role in drug discovery
	8 - Conclusion
	References
Chapter 9 - New strategies and targets for antibacterial discovery
	1 - Antimicrobial discovery strategies: a historical perspective
	2 - New approaches to mining novel natural compounds
		2.1 - Culturing the unculturable
		2.2 - Awakening silent or cryptic secondary metabolic pathways
			2.2.1 - Genome mining
			2.2.2 - Metagenomics-guided antimicrobial discovery
			2.2.3 - Ribosome engineering
			2.2.4 - One strain-many compounds approach
			2.2.5 - Modifying regulatory elements or promoter regions
			2.2.6 - Heterologous expression in engineered hosts
			2.2.7 - Combined-culture methods
	3 - Beyond traditional antibiotics
		3.1 - Antimicrobial peptides
		3.2 - Bacteriophages
		3.3 - Nanoparticles
	4 - Antimicrobial targets
		4.1 - New target identification strategies
		4.2 - Novel antimicrobial targets
			4.2.1 - Targeting virulence
			4.2.2 - Preventing microbial communication
			4.2.3 - Targeting two-component signal transduction systems
			4.2.4 - Efflux pumps
			4.2.5 - Fatty acid biosynthesis pathways as antimicrobial targets
			4.2.6 - Aminoacyl-transfer RNA synthases
	5 - Summary
	References
Chapter 10 - Importance of efflux pumps in subjugating antibiotic resistance
	List of abbreviations
	1 - Introduction
		1.1 - Mechanism of antibiotic resistance
		1.2 - Development of antibiotic resistance
	2 - Bacterial efflux system
		2.1 - Types of resistance
	3 - Efflux pump-mediated multidrug resistance
		3.1 - β-Lactams (extended spectrum β-lactamase)
		3.2 - Metallo β-lactamase
		3.3 - AmpC β-lactamase
	4 - Integrons
	5 - Other antibiotic resistance genes
	6 - Resistance mechanisms in Escherichia coli
		6.1 β-Lactams
		6.2 Aminoglycosides
		6.3 Trimethoprim
		6.4 Fluoroquinolones
		6.5 Sulfonamides
	7 - Families of efflux pumps
	8 - Types of efflux pump inhibitors based on their mechanism of action
		8.1 Energy dissipation
		8.2 Inhibition by direct binding
	9 - Types of efflux pump inhibitors based on their origin
		9.1 - Plant-derived efflux pump inhibitors
		9.2 - Efflux pump inhibitors of synthetic origin
		9.3 - Efflux pump inhibitors derived from microbes
	10 - Overcoming efflux-mediated antimicrobial resistance
	11 - Efflux pumps of important bacteria
		11.1 Staphylococcus aureus
		11.2 Escherichia coli
		11.3 Pseudomonas aeruginosa
	12 - Regulation of multidrug efflux pumps
		12.1 Significance of inhibitors as novel therapeutic agents
		12.2 Current challenges for efflux pump inhibitors as therapeutic agents
	13 - Future studies
	14 - Conclusion
	References
Chapter 11 - Phage therapy—bacteriophage and phage-derived products as anti-infective drugs
	1 - Introduction
	2 - Lysins—an overview
	3 - Development path for lysin drugs
		3.1 - Stage 1: identification of lysins
			3.1.1 - Design, construction, and characterization of chimeric lysin P128
				3.1.1.1 - Identification of ectolysin ORF56 from phage K
				3.1.1.2 - Construction of a potent antistaphylococcal chimeric ectolysin
				3.1.1.3 - Mechanism of action of P128
		3.2 - Stage 2: lysin characterization
			3.2.1 - Assessment, spectrum, and preclinical testing of P128
				3.2.1.1 - Assessment of the antimicrobial activity of P128
				3.2.1.2 - Spectrum of P128 activity
				3.2.1.3 - Preclinical efficacy and safety testing of P128
		3.3 - Stage 3: lysin manufacture
			3.3.1 - The chemistry, manufacturing, and controls for lysin P128
				3.3.1.1 - Overview
				3.3.1.2 - Manufacturing process development
				3.3.1.3 - Purification process
				3.3.1.4 - Analytical methods and specifications
		3.4 - Stage 4: clinical development
			3.4.1 - Preclinical studies: pharmacology/toxicology
			3.4.2 - Clinical development
				3.4.2.1 - Defining target medical condition
				3.4.2.2 - Target product profile
				3.4.2.3 - Target product profile for the systemic use of P128
	4 - Conclusion
	5 - Summary
	Acknowledgments
	References
Chapter 12 - Drug discovery targeting drug-resistant nontuberculous mycobacteria
	1 - The need for drug discovery targeting drug-resistant nontuberculous mycobacteria
		1.1 - Innate resistance of nontuberculous mycobacteria to antimicrobials
		1.2 - Challenges of nontuberculous mycobacteria drug development
		1.3 - New compounds tackling drug resistance
		1.4 - New targets for compound development
		1.5 - Existing antimicrobials being repurposed for nontuberculous mycobacteria treatment
		1.6 - Therapeutic vaccine approaches
	References
Chapter 13 - New strategies to combat drug resistance in bacteria
	Appendices and Nomenclatures
	1 - Introduction
		1.1 - Development of antimicrobial drugs
		1.2 - Spread of antibiotic resistance
		1.3 - Types of antibiotic resistance
		1.4 - Mechanisms of multidrug resistance
		1.5 - Antibiotics in the management of infections due to Gram-negative bacteria
	2 - Combating drug resistance
		2.1 - Antibiotic research in the age of omics
			2.1.1 - Transcriptomics
			2.1.2 - Proteomics
			2.1.3 - Genomics
		2.2 - Bioinformatics and high-throughput screening for antibiotics discovery
			2.2.1 - Genomics-based applications
		2.3 - Synthesis of nanomaterials
		2.4 - Phage therapy
		2.5 - Molecular targets and strategies to combat drug resistance in bacteria
			2.5.1 - Targeting essential processes
			2.5.2 - Targeting nonessential processes
	3 - Conclusion and future perspectives
	References