Bacterial Enzymes as Targets for Drug Discovery

Meeting the Challenges of Antibiotic Resistance

1st Edition - November 27, 2024
Imprint: Academic Press
Editors: Punit Kaur, Priyanka Sharma
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 2 2 2 2 2 - 1
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 2 2 2 1 - 4

Bacterial Enzymes as Targets for Drug Discovery: Meeting the Challenges of Antibiotic Resistance addresses the gap between medical microbiology, structural biology, and genomic sc… Read more

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Bacterial Enzymes as Targets for Drug Discovery: Meeting the Challenges of Antibiotic Resistance addresses the gap between medical microbiology, structural biology, and genomic science in the development of new antibacterial drug development. This book consolidates detailed profiling of bacterial target enzyme families for the drug discovery process and methodologies for use and validation of the potential drug targets. The contents cover the foundations of the antibiotic drug discovery process and focus on bacterial enzymes as drug targets, building across these disciplines to provide a comprehensive resource in bacterial structural biology and genomics. This is the ideal reference for antibiotic drug discovery researchers in the pharma industry and academia. Biochemists, microbiologists, and medicinal chemists will also benefit from this books’ content.

Title of Book
Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Section I. Primer of the antibiotic discovery process
Chapter 1. Understanding antimicrobial resistance
1 Antimicrobial resistance
2 Current scenario
3 Antimicrobial mechanism of action
3.1 Cell wall as antimicrobial target
3.2 Inhibition of DNA and RNA synthesis
3.3 Inhibition of protein biosynthesis
3.3.1 Inhibitors of 30S subunit
3.3.2 Inhibitors of 50S subunit
3.4 Folic acid metabolism inhibitors
4 Resistance mechanisms
4.1 Decrease in drug uptake
4.2 Modification of drug targets
4.3 Degradation of drug molecule
4.4 Drug modifications
4.5 Drug efflux
5 Emergence of antibacterial resistance
5.1 Selection pressure
5.2 Horizontal transfer of resistance genes
6 Strategies to control and combat antibiotic resistance
7 Conclusion
Chapter 2. Current scenario and future prospective of drug discovery and development against bacterial enzymes
1 Introduction
2 Available drugs and their mechanism of action
3 Cell wall biosynthesis inhibitors
4 Protein biosynthesis inhibitors
5 Membrane function inhibitors
6 Nucleic acid synthesis inhibitors
7 Metabolic pathway inhibitors
8 ATP synthase inhibitor
9 Experimental antibiotics
10 Current scenario of approved drugs and clinical drugs
11 Drug resistance
12 Dual inhibition as a novel strategy for antibiotic discovery
13 The advantages of dual inhibition are manifold
14 Future prospective
Chapter 3. Clinical diagnostics of bacterial infections and their resistance to antibiotics-Current state and novel enabling technologies implementation perspectives
1 Introduction
2 Conventional and culture-dependent methods
2.1 Pathogen detection using colony morphology
2.2 Pathogen detection using chromogenic media
2.3 Pathogen detection using biochemical techniques
2.4 Pathogen detection using microscopy techniques
2.5 Pathogen detection using MALDI-TOF
3 Culture-independent methods
3.1 Pathogen detection using polymerase chain reaction
3.2 Pathogen detection using ELISA
3.3 Pathogen detection using sequencing technologies
4 First-generation DNA sequencing
5 Second-generation or next-generation DNA sequencing
6 Third-generation DNA sequencing
7 The potential of DNA sequencing as a clinical diagnostic method
7.1 Pathogen detection using Raman spectroscopy
8 Conclusions_Point-of-care diagnostics
Chapter 4. An Odyssey into phylogeny, structural and functional conservation of novel antibacterial targets
1 Introduction
2 Antibiotic resistance mechanisms
3 How bioinformatics tools contribute in conservation studies and drug target prediction
4 Disease specific targets
4.1 Urinary tract infection
4.1.1 Carbapenem and its resistance
4.1.2 Structure of OXA-48
4.1.3 Conservation and prevalence of OXA-48
4.1.4 OXA-48-like enzymes
4.1.5 Mechanism of carbapenemase activity of OXA-48
4.1.6 Inhibitors and combination therapy against OXA-48
4.2 Typhoid
4.2.1 Shikimate pathway
4.2.2 Conservation of shikimate pathway in pathogenic bacteria
4.2.3 Inhibitors of enzymes involved in shikimate pathway
4.3 Tuberculosis
4.3.1 Qcr B
4.3.2 Isocitrate lyase
4.4 Pneumonia
4.4.1 Significance of cysteine
4.4.2 Serine acetyltransferase
4.4.3 O-acetyl serine sulfhydrylase
5 Conclusion
Conflict of interest
Chapter 5. Validation of drug targets using molecular methodologies and enzymatic activity assays for validation of inhibitory potential
1 Introduction
2 Methodologies used in the validation of drug targets
2.1 Genomics and transcriptomics approaches
2.1.1 Genomics approaches
2.1.2 Transcriptomics approaches
2.1.3 Gene expression profiling
2.1.4 Random transposon mutagenesis approach
2.1.5 CRISPR-Cas9
2.2 Proteomics approaches
2.2.1 Co-immunoprecipitation
2.2.2 Mass spectrometry
2.3 Structural biology approaches
2.3.1 X-ray crystallography
2.3.2 NMR spectroscopy
2.3.3 Cryo-EM
2.4 Bioinformatics approaches
2.4.1 Network analysis
2.4.2 Molecular modeling and docking
2.4.3 MD simulations
3 Enzymatic activity assays for inhibitory potential
3.1 Biochemical assays
3.2 High-throughput screening
3.3 Microbiological assays
3.3.1 Minimum inhibitory concentration assay
3.3.2 Disk diffusion assay
3.3.3 Time-kill assay
3.4 Biophysical assays
3.4.1 Surface plasmon resonance spectroscopy
3.4.2 Isothermal titration calorimetry
3.4.3 Differential scanning calorimetry
3.4.4 Enzyme kinetics assays
3.4.5 Fluorescence polarization
3.4.6 Microscale thermophoresis
3.4.7 Affinity chromatography
3.4.8 Immunoprecipitation
3.4.9 ELISA
3.4.10 AlphaScreen
3.4.11 Biolayer interferometry
3.4.12 Förster resonance energy transfer
4 Summary and outlooks
Chapter 6. Computational tools to identify potential drug targets in bacteria
1 Introduction
2 Exploring attractive targets in pathogenic bacteria
3 Essential and nonessential bacterial targets
4 Druggability assessment in structural models
5 Core genome analysis
6 Data integration for accurate metabolism models
7 Human and microbiota off-targets
8 Web-based tools for identifying pathogenic targets
9 Prioritizing targets: Applications in Bartonella bacilliformis and Klebsiella pneumoniae
10 Conclusions
Chapter 7. Antimicrobial drug resistance and bypassing strategies
1 Antibiotic resistance
2 Drug target associated mechanisms of resistance
2.1 Target site modification
2.1.1 Chromosomal mutation
2.1.2 Enzymatic protection of target
2.2 Target bypass
3 Drug associated mechanisms of resistance
3.1 Drug inactivation
3.1.1 β-lactamases based inactivation
3.1.2 Enzymatic modification of drug molecule
3.2 Reducing the intracellular concentration of drug
3.2.1 Reduced influx
3.2.2 Increased efflux
3.3 Biofilms
4 Strategies to bypass antimicrobial drug resistance
4.1 Antibiotic–antibiotic combination
4.2 Antibiotic–adjuvant combination
4.2.1 Inhibitors of bacterial enzymes
4.2.2 Efflux pump inhibitors
4.2.3 Teichoic acid biosynthesis inhibitors
5 Conclusion
Section II. Bacterial enzymes as drug targets
Chapter 8. Designing tomorrow's antibiotics: Cutting-edge strategies and technologies
1 Antimicrobial resistance: Charting the course against superbugs
2 Use of technological advancements: Mapping the pathways to pave the path
3 Breaking down barriers: Antiresistance strategies
3.1 Combination therapy
3.2 Targeting the resistance mechanisms
3.3 Bypassing resistance
3.4 RNA silencing
3.5 CRISPR-Cas system
3.6 Drug repurposing
4 Beyond conventional methods: Alternative approaches to antimicrobial therapy
4.1 Targeting the virulence factors
4.2 Antimicrobial peptides
4.3 Nanoparticles
4.4 Photosensitizing
4.5 Phage therapy
4.6 Immunoinformatics
5 Other nonconventional alternatives
6 Conclusion and future prospective
Chapter 9. Topoisomerases as targets for halting bacterial DNA replication
1 Introduction
2 Role of topoisomerases in DNA replication
3 Types of topoisomerases and their function
3.1 Type I topoisomerase
3.1.1 Eubacterial Topo I
3.1.2 Topoisomerase III
3.1.3 Reverse gyrase
3.2 Type 1B topoisomerase
3.2.1 Type 1C topo (TopoV)
4 Type II topoisomerases
4.1 Type IIA topoispmerases
4.1.1 DNA gyrase
4.1.2 Organization of DNA gyrase
4.1.3 Gyrase specificity to DNA substrates
4.1.4 Mechanism of action of DNA gyrase
4.1.5 DNA cleavage reaction of gyrase
4.2 Topo IV
5 Type II B topo
5.1 Topo VI
5.2 Topo VIII
6 Topoisomerase inhibitors
6.1 Topo I inhibitors
6.2 Topoisomerase II inhibitors
7 Quinolone and their derivatives
7.1 Mode of action of quinolones
7.2 Quinolone resistance
7.2.1 Quinolone resistance due to mutation alteration in target enzymes
7.2.2 Quinolones resistance due to over-expression of efflux pump
7.2.3 Plasmid-mediated resistance to quinolones
7.3.1 Microcin B17 (MccB17)
7.3.2 CcdB
7.3.3 Pentapeptide repeats proteins (Qnr and MfpA)
7.3.4 GyrI
8 Novel bacterial topoisomerase inhibitor (NBTI)
9 Gyrase inhibitors in clinical trials
10 Natural inhibitors of DNA gyrase
10.1 Aminocoumarins
10.2 Simocyclinone
10.3 Cyclothialidines
10.4 Catechin-based polyphenols (from green tea)
10.5 Clerocidin
10.6 Haloemodin
10.7 Chebulinic acid
10.8 Albicidins
11 Progress and failures of gyrase inhibitors
12 Conclusion
Chapter 10. Lactamase and antibiotic resistance: A catalyst for drug discovery breakthroughs
1 Introduction
2 History of β-lactam antibiotic discovery
2.1 Penicillin
2.2 Expansion of the β-lactam antibiotic family
2.3 Semisynthetic antibiotics
3 β-lactamase
3.1 Classification of β-lactamases
3.1.1 Class A β-lactamases
3.1.2 Class B β-lactamases
3.1.3 Class C β-lactamases
3.1.4 Class D β-lactamases
3.2 Mechanisms of β-lactamase action
3.2.1 Serine-based hydrolysis in Class A, C, and D
3.2.2 Metallo-β -lactamase (MBL) (Class B)
3.2.3 Substrate specificity
4 β-lactam antibiotic resistance
4.1 Resistance mechanism
4.1.1 Role of β-lactamases in antibiotic resistance
4.1.2 Horizontal gene transfer (HGT)
4.1.3 Coresistance and coselection
4.1.4 Strategies for overcoming β-lactamase-mediated resistance
5 Steps in drug discovery against β-lactamases
6 β-lactamase inhibitors and novel β-lactam drugs (BLI)
6.1 Avibactam
6.2 Aztreonam
6.3 Cefiderocol
6.4 Ceftaroline
6.5 Ceftobiprole
6.6 Durlobactam
6.7 Enmetazobactam
6.8 Nacubactam
6.9 Taniborbactam
6.10 Vaborbactam
6.11 Zidebactam
7 Conclusion
8 Future prospectives
Chapter 11. Selective versus broad-spectrum inhibition of novel outer membrane targets in Gram-negative bacteria
1 Introduction
2 Background/current state of antimicrobial resistance treatment
3 Selective versus broad-spectrum outer membrane proteins and complexes as antimicrobial targets in Gram-negative bacteria
3.1 Selective OMPs
3.1.1 Porin inhibitors
3.1.2 Iron transport protein inhibitors
3.2 Broad-spectrum OMPs
3.2.1 BamA
4 Challenges and future directions
5 Conclusion
Author contributions
Chapter 12. Ribosome binding antibacterial agents
1 Introduction
2 The ribosome and translation as antibiotic targets
3 Antibacterial compounds specific to the 50S subunit
3.1 Proline-rich peptide antibacterial agents bind the ribosome
3.1.1 Type I proline-rich antimicrobial peptides
3.1.2 Type II proline-rich antimicrobial peptides
3.2 Klebsazolicin obstructs the ribosomal exit tunnel
3.3 Thiopeptides that affect the binding of translation factor
4 Antimicrobial compounds that target 30S subunit
4.1 Edeine inhibits the formation of the initiation complex
4.2 GE81112 inhibits translation initiation
4.3 Dityromycin inhibits the elongation process
4.4 Capreomycin and viomycin inhibit translocation
4.5 Odilorhabdins tether ribosomes and tRNA
4.6 Kasugamycin prevents the interaction of mRNA with the small subunit of the ribosome
5 The structural aspect of antibiotic-ribosome interaction
6 Ribosome-binding antibiotics increase bacterial longevity and growth efficiency
7 Antibiotic resistance mechanism
7.1 Mechanism of tetracycline resistance
7.2 Mechanism of aminoglycoside resistance
7.3 Mechanism of ketolide, lincosamide, macrolide, and streptogramin resistance
8 Connection between antibiotics and drug design
9 Genomics in antibiotic development
9.1 Structural scaffolds and genomic screening
9.2 Human microbiome as a source
9.2.1 Commendamide
9.2.2 Humimycins
9.2.3 Lactocillin
9.2.4 Ludgunin
9.3 Genome mining for translation inhibitors
10 Advancements in antibiotic action analysis
10.1 Ribo-seq for codon information
10.2 Toeprinting for proper localization
10.3 Advances in single-molecule technology
10.3.1 Ribosome conformational changes
10.3.2 Ribosome–mRNA interactions
10.3.3 Ribosome–tRNA interactions
10.3.4 Effect of translation factors
10.4 Crystallography and cryo-EM for advanced information
11 Conclusion and future perspectives
Chapter 13. Targeting RNA polymerase: A key approach for designing novel antimicrobial therapeutic strategies
1 Introduction
2 RNAP structure and function
2.1 Structure
2.2 Overview of the transcription cycle
3 RNAP inhibitors
3.1 The primary channel inhibitors
3.2 Switch region inhibitors
3.3 Active center inhibitors
3.4 Secondary channel inhibitors
3.5 Transcription termination inhibitors
3.6 Sigma factor interaction inhibitors
3.7 Nucleoside analogues
3.8 Compounds with unrecognized target sites
4 Conclusion and future prospective
Chapter 14. Colistin resistance and strategies against superbug, where we are?
1 Introduction
2 The global spread of colistin resistance
3 Understanding colistin resistance
4 Clinical implications
5 Case studies and success stories
6 Surveillance and detection of colistin resistance
6.1 Challenges in timely identification of colistin-resistant strains
6.2 Molecular techniques for detecting colistin resistance genes
7 Strategies against colistin-resistant superbugs
7.1 Antibiotic combination therapies
7.2 Novel drug development targeting alternative bacterial enzymes
7.3 Nontraditional approaches
8 Conclusion
Chapter 15. Deoxythymidine triphosphate pathway enzymes as an antibacterial target
1 Introduction
1.1 Bacteria have become resistant to drugs through various mechanisms
1.1.1 Limiting drug uptake
1.1.2 Drug efflux
1.1.3 Chemical modification of drug
1.1.4 Destroying the drug
1.1.5 Drug target modification
2 Inhibition of bacterial dUTPase
3 Structure and inhibitor development of classical thymidylate synthase
3.1 Flavin-dependent thymidylate synthase, ThyX
4 Thymidylate kinase inhibitors
5 Nucleoside diphosphate kinase
6 Current prospects
Chapter 16. Arresting the peptidoglycan synthesis to kill the bacteria
1 Introduction
2 Antibiotics targeting PGS significantly enhance the diameter of FtsZ-ring
3 Inhibition of septum constriction by lipid II binding glycopeptides
4 Oxacillin interferes in septum constriction during cell division stage
Chapter 17. Clp protease complex as a therapeutic target for tuberculosis
1 Introduction
1.1 The Clp complex: An overview
1.2 Essentiality of Clp complex in mycobacteria
2 Clp protease family in M. tuberculosis
2.1 ClpP, proteolytic subunit
2.2 AAA+ ATPase subunits
2.2.1 ClpX
2.2.2 ClpC
2.2.3 ClpA
2.2.4 ClpYQ
2.3 Other regulatory proteins
2.3.1 Adapter proteins
2.3.2 Chaperones
2.4 Clp as a drug target in M. tuberculosis
2.5 Clp inhibitors
3 Conclusions
Author contributions
Chapter 18. PlaF: A bacterial lands cycle phospholipase A mediating membrane phospholipid degradation and virulence adaptation∗
1 Introduction
2 Discovery of PlaF
3 Optimized production of PlaF in homolog host resulted in stable and active enzyme
3.1 Purification and biochemical characterization of PlaF
4 PlaF is a cytoplasmic membrane-bound phospholipase A1
5 Remodeling membrane lipid composition: PlaF is putative bacterial lands cycle phospholipase A
6 Medium-chain FAs are detected in P. aeruginosa in free form and likely originate from glycerophospholipid hydrolysis
7 Phospholipid homeostasis is affected in P. aeruginosa ΔplaF
8 PlaF is a novel virulence factor of P. aeruginosa affecting swimming motility and biofilm formation
9 Virulence function of PlaF is linked to modulation of lipidome and proteome
10 Crystal structure of PlaF homodimer
11 PlaF crystal structure indicates a specific membrane orientation
12 A network of ligand-mediated interactions connects the dimerization and active sites
13 Dimerization affects PlaF activity
14 Medium chain FAs induce dimerization and inhibit PlaF activity
15 Conclusions
Chapter 19. Bacterial TIR domain-containing proteins as drug targets
1 Introduction
2 Bacterial Toll/interleukin-1 receptor domains as virulence factors
3 Bacterial Toll/interleukin-1 receptor proteins have roles in antiviral immunity
4 Molecular and structural basis of bacterial Toll/interleukin-1 receptor domain-based biological activities
5 Bacterial Toll/interleukin-1 receptor domains as antibacterial drug targets
6 Conclusions
Chapter 20. Drug repurposing: Tackling antibiotic resistance with existing therapeutics
1 Introduction
2 Antibiotic resistance
2.1 Cause of antibiotic resistance
2.2 Tackling antibiotic resistance
3 Drug repurposing: Story so far
3.1 Advantages of drug repurposing
3.2 Categories of repurposed drugs
3.3 Approaches of drug repurposing
3.4 Challenges of drug repurposing
4 Targeting bacterial enzymes for drug repurposing
5 Conclusion
List of abbreviations
Index

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Bacterial Enzymes as Targets for Drug Discovery

Meeting the Challenges of Antibiotic Resistance

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Punit Kaur

Priyanka Sharma

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