Antibiotic Drug Discovery: New Targets and Molecular Entities

285 Pages·2017·14.27 MB·English

by  Steven M Firestine

Antibiotic Drug Discovery
New Targets and Molecular Entities
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Drug Discovery Series
Editor-in-chief
David Thurston, King’s College, UK
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F David Fox, Vulpine Science and Learning, UK
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87 Ana Martinez, Centro de Investigaciones Biologicas-CSIC, Spain
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62 David Rotella, Montclair State University, USA
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78 Sarah Skerratt, Convergence, UK
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1 Hong Shen, Roche Innovation Center Shanghai, China
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g | d Titles in the Series:
or 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
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s.rs 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
ub 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
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p:// 4: Accounts in Drug Discovery
htt 5: New Frontiers in Chemical Biology
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o 6: Animal Models for Neurodegenerative Disease
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01 7: Neurodegeneration
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y 8: G Protein-Coupled Receptors
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9 9: Pharmaceutical Process Development
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n 10: Extracellular and Intracellular Signaling
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d 11: New Synthetic Technologies in Medicinal Chemistry
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blis 12: New Horizons in Predictive Toxicology
u 13: Drug Design Strategies: Quantitative Approaches
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14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
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31: Traditional Chinese Medicine
32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
34: Emerging Drugs and Targets for Parkinson's Disease
01 35: Pain Therapeutics; Current and Future Treatment Paradigms
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FP 36: Biotherapeutics: Recent Developments using Chemical and Molecular
70- Biology
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29 37: Inhibitors of Molecular Chaperones as Therapeutic Agents
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82 38: Orphan Drugs and Rare Diseases
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81 39: Ion Channel Drug Discovery
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9/9 40: Macrocycles in Drug Discovery
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0 41: Human-based Systems for Translational Research
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10. 42: Venoms to Drugs: Venom as a Source for the Development of Human
doi: Therapeutics
g | 43: Carbohydrates in Drug Design and Discovery
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c. 44: Drug Discovery for Schizophrenia
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s.r 45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
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http:// 46: Green Chemistry Strategies for Drug Discovery
n 47: Fragment-Based Drug Discovery
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17 48: Epigenetics for Drug Discovery
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M 50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
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1 Evaluation
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d o 51: Nanomedicines: Design, Delivery and Detection
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h 52: Synthetic Methods in Drug Discovery: Volume 1
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54: Drug Transporters: Role and Importance in ADME and Drug
Development
55: Drug Transporters: Recent Advances and Emerging Technologies
56: Allosterism in Drug Discovery
57: Anti-aging Drugs: From Basic Research to Clinical Practice
58: Antibiotic Drug Discovery: New Targets and Molecular Entities
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Antibiotic Drug Discovery
New Targets and Molecular Entities
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29 Edited by
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81 Steven M. Firestine
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9/9 Wayne State University, Detriot, USA
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c. Troy Lister
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97 Drug Discovery Series No. 58
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10 Print ISBN: 978-1-78262-424-0
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1 PDF eISBN: 978-1-78262-987-0
doi: EPUB eISBN: 978-1-78801-149-5
g | ISSN: 2041-3203
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s.rs A catalogue record for this book is available from the British Library
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p://p © The Royal Society of Chemistry 2017
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01 Apart from fair dealing for the purposes of research for non-commercial purposes or for
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0-F Preface
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10 The introduction of penicillin 75 years ago ushered in, arguably, the greatest
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1 advancement in the history of medicine. Its discovery by Fleming and
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org | others contributed significantly to the Allied war effort saving many thousands
sc. of lives. The broad application of penicillin during and after World War II
bs.r demonstrated the great benefit antibiotics provided the medical community
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p:// in treating surgical-, wound-, skin- and systemic-based infections. The con-
htt tinued discovery and development of antibiotics throughout the 1950’s to the
on 1970’s bolstered the number of new therapeutics available to doctors to treat
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1 a wide variety of infections. This golden age of antibiotic discovery resulted
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y in generations of humans that never feared acquiring a life-threatening
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M infection. Indeed, antibiotics performed so well through the later part of the
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n 1 20th century that many people in the industrialized world have forgotten
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d the significant threat that bacterial infections pose to humans. Infectious
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sh disease was the second leading cause of death in the United States prior to
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marily driven by neglected tropical infections in the developing world). Thus,
despite the tremendous discovery and innovation in the field of infectious
disease medicine over the past seven decades, bacterial infections remain a
significant worldwide scourge.
Even with the successes achieved from 1950–2000, the turn of the century
has seen a significant increase in antibiotic-resistance and a heightened
awareness of the emergent threat. Antibiotic resistance has always existed.
Indeed, resistance to penicillin was detected only a few years after its intro-
duction into clinical practice. Yet, this problem is now more severe because
of the rise of resistance in pathogenic bacteria and because we are begin-
ning to identify bacteria that are resistant to all currently available classes of
Drug Discovery Series No. 58
Antibiotic Drug Discovery: New Targets and Molecular Entities
Edited by Steven M. Firestine and Troy Lister
© The Royal Society of Chemistry 2017
Published by the Royal Society of Chemistry, www.rsc.org
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viii Preface
antibiotics. This is particularly troubling because historically, resistance was
dealt with by simply switching to another antibiotic. The rise of multi-drug-
resistant organisms renders this method of treatment challenging and risky
for clinicians.
How did we get here? There are a multitude of factors that played a role.
07 The previously mentioned success in identifying new antibiotics cultivated
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FP hubris in thinking that the infectious microbial world had or could be con-
70- quered. Economics also played a major role. Many large pharmaceutical com-
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29 panies exited infectious disease drug discovery as research and development
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82 became increasingly expensive, protracted clinical trials slowed development
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81 and the expectation by payers and the public that antibiotics should be low
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9/9 cost hindered a return on investment. The scientific community too grew
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0 weary of a growing list of failed drug discovery and development campaigns,
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10. the lack of novel targets and the feeling that nothing innovative remained to
doi: be uncovered in antibiotic drug discovery. Lastly, governments worldwide
g | were slow in appreciating the threat posed by antimicrobial resistance and
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c. historically have done little to facilitate the advancement of therapeutics.
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s.r These contributing factors have stymied investment in and discovery of
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http:// resistant infections.
n As a result, in 2017, we have arrived at a point where there are few treat-
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17 ment options for many Gram-negative infections, where methicillin-resistant
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1 mortal. Subsequently, clinicians are being forced to resort to older, less
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d o well-tolerated drugs to treat resistant microbes. The global community is
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financial burden on health-care systems worldwide. A second golden age of
antibiotic drug discovery is desperately needed.
There have been many recommendations for addressing antibiotic resis-
tance including new stewardship control measures, better hygiene, and
new methods to identify at-risk patients. Indeed, several valuable, recent
initiatives have been started by the U.S. and European governments and reg-
ulators to dramatically speed up and reduce the cost antibiotic drug devel-
opment and many incentives are now available for these pursuits. However,
almost everyone that has sought to address this problem agrees that the
long-term solution is discovery and introduction of new antibiotic targets
and new chemical matter that leads to novel therapeutics. This book pres-
ents the latest advancements to this end. The eight chapters in this book
provide an exciting discussion of novel targets in purine and isoprenoid
biosynthesis, lipopolysaccharide transport, and biofilm production. Also
included are reviews of unique targets in tuberculosis and Clostridium dif-
ficile infections, narrow spectrum antibiotics, as well as a discussion of a
new antibiotic isolated from soil bacteria. The chapters focus on targets
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Preface ix
and inhibitors that are not clinically used, but represent new approaches
towards the treatment of resistant infections. It is our hope that the reader
will draw inspiration from this collection of scientific advancements and
join the critical effort to discover and develop the next era of antibiotics. We
are certain that without these new innovations, the next 75 years will not be
07 as healthy as the last.
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1 1.6.1 Anti-Toxins 10
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Chapter 2 Targeting Purine Biosynthesis for Antibacterial
Drug Design 20
Gyan Modi, Shibin Chacko and Lizbeth Hedstrom
2.1 Introduction 20
2.1.1 The De novo Purine Nucleotide Biosynthesis
Pathway 21
2.1.2 The Purine Conversion Pathways 22
2.1.3 The Purine Salvage Pathways 24
2.1.4 Availability of Purine Bases and Nucleosides 25
Drug Discovery Series No. 58
Antibiotic Drug Discovery: New Targets and Molecular Entities
Edited by Steven M. Firestine and Troy Lister
© The Royal Society of Chemistry 2017
Published by the Royal Society of Chemistry, www.rsc.org
xi