About Book

Since their discovery, antimicrobial drugs have proved remarkably effective for the control of bacterial infections. However, it was soon evident that bacterial pathogens were unlikely to surrender unconditionally, because some pathogens rapidly became resistant to many of the first effective drugs. Antimicrobial resistance refers to the stage when microbes evolve and become resistant to pharmaceutical drugs and medication. The resistance can take place via three ways, which are natural resistance, resistance acquired from other organisms and genetic mutation. A significant concern is that AMR could lead to a post-antibiotic era in which antibiotics would no longer work. Both microbial behaviour and the way in which people take antimicrobial drugs are responsible for the increase in AMR. Antibiotic resistance has the potential to affect people at any stage of life, as well as the healthcare, veterinary, and agriculture industries, making it one of the world’s most urgent public health problems. This book provides comprehensive insights into the field of antimicrobial resistance. The topics included in this book are of utmost significance and are bound to provide incredible insights to readers. It explores molecular characterization, drug targeting, drug synergy, drug resistance, molecular determinants, multidrug resistance, apoptosis versus autophagy and mechanisms of drug resistance, resistance reversion and anticancer drug screening. As this field is emerging at a rapid pace, the contents of this book will help the readers understand the modern concepts and applications of the subject. It aims to serve as a resource guide and facilitate the study of the discipline.

Preface............................................................................................................v

Chapter 1 Chemoresistance of Lung Cancer Cells: 2D and 3D In Vitro Models for Anticancer Drug Screening................................................................1

Abstract...................................................................................................1

1. Introduction............................................................................................1

2. In vitro models for anticancer drug screening...............................4

3. Implications for translational oncology..........................................16

4. Conclusions..........................................................................................16

Acknowledgements.............................................................................17

Chapter 2 Clade-Specific Distribution of Antibiotic Resistance Mutations in the Population of Mycobacterium tuberculosis - Prospects for Drug Resistance Reversion................................................................................28

Abstract.................................................................................................28

1. Introduction..........................................................................................29

2. Genetic mechanisms of drug resistance in Mtb...........................30

3. Drug-resistance against the background of Mtb genetic clades

and current diagnostic approaches.................................................34

4. Non-random associations between polymorphic sites in genomes

of M. tuberculosis........................................................................................38

5. The concept of the drug resistance reversion and implementation

thereof....................................................................................................43

6. Conclusion............................................................................................46

Acknowledgements.............................................................................47

Chapter 3 Drug Resistance in Mycobacterium tuberculosis...............................53

Abstract.................................................................................................53

1. Introduction..........................................................................................54

2. Mutations that confer resistance in

Mycobacterium tuberculosis.............................................................54

3. Searching for new markers to identify drug resistance of

Mycobacterium tuberculosis.............................................................59

4. Development of new drugs against Mycobacterium tuberculosis

drug resistance strains.......................................................................61

Acknowledgements.............................................................................62

Chapter 4 Different Mechanisms of Drug Resistance in Myelodysplastic

Syndromes and Acute Myeloid Leukemia.........................................68

Abstract.................................................................................................68

1. Introduction..........................................................................................69

2. Treatment options...............................................................................70

3. Drug resistance of MDS and AML patients..................................72

4. Perspectives..........................................................................................81

Acknowledgements.............................................................................81

Chapter 5 Drug Resistance and Molecular Cancer Therapy: Apoptosis Versus

Autophagy...................................................................................................92

1. Introduction..........................................................................................92

2. Apoptosis pathways...........................................................................93

3. IAP family proteins promote apoptosis-resistance .....................95

4. XIAP is a potent caspase inhibitor..................................................95

5. cIAP regulation of the NF-κB signaling pathway ....................96

6. SMAC: IAP-antagonist ....................................................................98

7. BCL-2 family proteins regulate the intrinsic apoptotic

pathway..............................................................................................103

8. Autophagy and autophagic cell death: background ................110

9. The role of autophagy in therapy resistance..............................117

10. Re-sensitization of cancer cells to treatment by

autophagy inhibition........................................................................118

11. Concluding remarks ........................................................................118

Acknowledgement ...........................................................................119

Chapter 6 Complex Regulatory Interplay Between Multidrug Resistance and Oxidative Stress Response in Yeast: The FLR1 Regulatory Network as a Systems Biology Case-Study.......................................................144

1. Introduction........................................................................................144

2. The multidrug resistance network in yeast.................................145

3. The role of yap1 in multidrug resistance in yeast ...................147

4. The role of the pdr network in oxidative stress response.......150

5. Cross-talk between multidrug resistance control and oxidative

stress response in pathogenic yeasts ...........................................152

6. The combinatorial regulation of the multidrug transporter Flr1:

A systems biology case-study........................................................154

7. Conclusion and perspectives..........................................................158

8. Acnowledgements.............................................................................159

Chapter 7 Drug Synergy – Mechanisms and Methods of Analysis..............167

1. Introduction........................................................................................167

2. Basic models and mechanisms – Synergy on a molecular

level......................................................................................................168

3. Mechanisms and techniques of synergy testing in complex

biomedical settings .........................................................................182

4. Borderlines of synergism – Potentiation, coalism, inertism,

metabolic interference .....................................................................191

Chapter 8 Drug Targeting in IBD Treatment – Existing and New Approaches...............................................................................................198

1. Introduction........................................................................................198

2. Conventional design strategies for GI targeting .......................199

3. Disease oriented strategies for drug targeting in IBD .............209

4. Specific colon targeting ..................................................................221

5. Biological and gene therapies for inflammatory bowel

diseases ..............................................................................................224

6. Acknowledgments ...........................................................................227

Citation......................................................................................................243

Index...........................................................................................................245

About Author

Aleksei Williamson pursued his M.Sc. in Ecology and Evolutionary Biology from State University, Barnaul. His primary areas of scholarly and research interests lie in the fields of antibiotic resistance, evolutionary biology and microevolution. He is a Guest Lecturer at a Public University, Opava. He has travelled and lectured extensively throughout Europe and United States; primarily for higher education. He has won several awards for his knowledge and teaching contributions to antibacterial resistance. He has been presented the “Distinguished Contributions to Lifelong Learning” award for his phenomenal service and the impact he has made.