Systems Biological Approaches in Infectious Diseases (eBook)

Foreword 8
Systems biology and its impact on anti- infective drug development 11
1 Introduction 12
2 Data for systems biology: ‘Omics, images and chemistry 14
3 Makingmodels 16
4 Networks 18
5 Integrative systems biology 23
6 New targets for anti-infective drug development 24
References 26
Applications of transcriptional profiling in antibiotics discovery and development 30
1 Introduction 31
2 Transcriptional profiling – highly parallel measurement of gene expression 32
3 Comparison of the capabilities of transcriptomics and proteomics 35
4 The importance of experimental design and integrated data analysis systems 35
5 Discovering therapeutic targets 37
6 Forward pharmacology 40
7 Developing reporter assays for pathway-specific compound screens 43
8 Improving the compound selection and optimization process 45
9 Assessing drug safety and toxicology 47
10 Conclusion 48
References 50
Chemical genetics: An evolving toolbox for target identification and lead optimization 56
1 Genomic approaches to identifying drug targets 57
2 The genomic interface of chemistry and biology: Chemical genetics 58
3 Conclusion: Chemical genetics and drug development 78
References 78
Proteomic profiling of cellular stresses in Bacillus subtilis reveals cellular networks and assists in elucidating antibiotic mechanisms of action 84
1 Introduction 85
2 The tools of proteomic profiling 87
3 Proteomic contributions to understanding bacterial physiology 91
4 Proteomics in antibacterial drug discovery 95
References 102
Elucidating the mode- of- action of compounds from metabolite profiling studies 106
1 Introduction 107
2 Microbial metabolite profiling 108
3 Novel drug discovery 121
4 In vivo metabolic fluxes 122
5 Metabolites in systems biology 124
References 126
A subsystems-based approach to the identification of drug targets in bacterial pathogens 132
1 Introduction 133
2 Stage I: Choosing target subsystems. Genome- scale essentiality and conservation analysis 136
3 Stage II: Analyzing target subsystems. Metabolic reconstruction and functional predictions 146
4 Stage III: Selecting target genes. Target prioritization and validation 158
5 Concluding remarks: From targets to drugs 162
References 164
Metabolic control analysis to identify optimal drug targets 171
1 Introduction 172
2 Mathematical models: Assistants for the human brain 173
3 Metabolic control analysis: Basic principles 175
4 Effective drug target identification using MCA 179
5 Enhancing anti-parasite drug selectivity with differential control analysis 180
6 Control of tumor cell growth 183
References 185
The protein network as a tool for finding novel drug targets 189
1 Protein linkages 190
2 Biochemical methods to identify protein-protein interactions 190
3 Computational methods to identify protein linkages 192
4 Protein networks 195
5 Drug targets 203
6 Conclusion 207
References 208
Toxicogenomics applied to predictive and exploratory toxicology for the safety assessment of new chemical entities: a long road with deep potholes 213
1 Overview 214
2 Toxicogenomics 216
3 Conclusion 229
References 230
Biological robustness in complex host- pathogen systems 234
1 Robustness is a fundamental organizational principle of biological systems 235
2 Four underlying general mechanisms for robustness 237
3 Intrinsic features of robust systems: Evolvability and trade- offs 239
4 Robustness attributes of pathogens 241
5 Limits of a robust system: Pathogen-triggered diseases 244
6 Does microbial flora affect vulnerability against pathogenic infections? 248
7 Future directions 250
References 251
Toward whole cell modeling and simulation: Comprehensive functional genomics through the constraint- based approach 258
1 Introduction to modeling using the constraint- based approach 259
2 Building a constraint-based model 262
3 Metabolic model applications and computational challenges 276
4 Future directions for constraint-based modeling 283
5 Conclusions 294
References 294
Genomics of host- pathogen interactions 302
1 Introduction 303
2 Functional genomics of bacterial pathogens 303
3 RNA profiling of host cells after infections 317
4 Functional genomics and drug discovery 321
References 324