Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery
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Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery
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Author : Jesse Jones
language : en
Publisher:
Release Date : 2019
Investigation Of Narrow Spectrum Targets In Antibacterial Drug Discovery written by Jesse Jones and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019 with categories.
Background: Significant concerns are associated with the use of broad-spectrum antibacterial agents, including collateral eradication of beneficial bacteria from the human microbiome, the onset of antibacterial-associated infections, and continued emergence of antibacterial drug resistance. As such, a critical need for novel and selective antibacterial targets exists. The investigation of two such targets, each pertaining to the highly concerning infections caused by streptococcal species and Clostridioides difficile, are presented herein. Bacterial topoisomerase I represents a potentially promising narrow-spectrum target as studies have arisen demonstrating its essentiality in bacterial species lacking the only other type IA topoisomerase (topoisomerase III). Additionally, recent studies demonstrating the essentiality of the fabK gene expressing enoyl-ACP reductase II (FabK) in C. difficile indicate its significant potential as a narrow-spectrum target. Presented here are data characterizing and validating both the TopoI and FabK enzymes as novel antibacterial targets via the implementation of an array of drug discovery techniques, including structural studies, biochemical assay development and application, and inhibitor screening and testing. Methods: An assortment of drug discovery techniques were employed for the targeting of SmTopoI and CdFabK, including different protein expression and purification techniques; X-ray crystallography; various biophysical and biochemical techniques for target characterization, validation, and drug screening; and different lead development and optimization studies. Results: The respective genes for SmTopoI and CdFabK have been cloned, and the expression and purification of various constructs of each target have been carried out and optimized for further analysis. The crystal structure of SmTopoI_N65 has been determined to 2.06 Å and diffracting CdFabK crystals (3.5 Å) have been attained. A high-throughput plate-based biochemical fluorescence kinetic assay has been optimized for screening against the CdFabK enzyme. Furthermore, activity and modality of inhibition assessment of small-molecule inhibitors of the CdFabK enzyme have been conducted, including phenylimidazole and benzothiazole compounds. Phenylimidazole analogues have been found to display micromolar inhibitory activity against CdFabK, and a benzothiazole analogue has been found to display nanomolar inhibitory activity against the target. Conclusions: The SmTopoI and CdFabK enzymes present potentially novel, narrow- spectrum antibacterial drug targets, and substantial progress has been made toward the rational targeting of these two enzymes. Of particular note, the first structure of a Topo I fragment from a gram-positive organism, S. mutans, has been determined. Enzymology and inhibitor studies have been conducted supporting the druggability of CdFabK and indicating the potential for selective inhibition of CdFabK.
Antibiotic Drug Discovery
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Author : Steven M Firestine
language : en
Publisher: Royal Society of Chemistry
Release Date : 2017-05-19
Antibiotic Drug Discovery written by Steven M Firestine and has been published by Royal Society of Chemistry this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-05-19 with Medical categories.
Recent years have seen a resurgence of antibiotic drug discovery. This book brings together the relevant information to assess the state-of-the-art. It identifies and elaborates the most recent and compelling strategies for antibiotic drug discovery with a primary focus on new targets, mechanisms and molecular entities. Addressing the need for continued investment in antibiotic drug development, the book provides a point of reference for the rapidly expanding infectious disease research community. In addition to its attention on new targets, the book focusses on the medicinal chemistry and chemistry of the targets. Within this framework, chapters from leading researchers in academia and industry address findings in important areas such as biofilm production, narrow spectrum antibiotics and novel antibacterials from previously uncultured soil bacteria. This book will be a useful resource for postgraduate students and researchers in medicinal chemistry wishing to understand the latest approaches to antibiotic drug discovery.
Treating Infectious Diseases In A Microbial World
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Author : National Research Council
language : en
Publisher: National Academies Press
Release Date : 2006-01-03
Treating Infectious Diseases In A Microbial World written by National Research Council and has been published by National Academies Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006-01-03 with Medical categories.
Humans coexist with millions of harmless microorganisms, but emerging diseases, resistance to antibiotics, and the threat of bioterrorism are forcing scientists to look for new ways to confront the microbes that do pose a danger. This report identifies innovative approaches to the development of antimicrobial drugs and vaccines based on a greater understanding of how the human immune system interacts with both good and bad microbes. The report concludes that the development of a single superdrug to fight all infectious agents is unrealistic.
New Antibiotic Targets
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Author : W. Scott Champney
language : en
Publisher: Springer Science & Business Media
Release Date : 2008-01-15
New Antibiotic Targets written by W. Scott Champney and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008-01-15 with Medical categories.
This book examines specific techniques which can be used to explore new drug targets and the effectiveness of new antibiotics. By testing new antimicrobial agents and modified existing drugs, the most vulnerable cell processes, such as cell wall and membrane synthesis, DNA replication, RNA transcription and protein synthesis, can be better exploited. This in-depth volume, however, delves even deeper by identifying additional novel cellular targets for these new therapies. The book will provide laboratory investigators with the vital tools they need to test the antimicrobial potential of products and to curb the rise of so many infectious diseases.
Antibiotic Discovery And Development
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Author : Thomas J. Dougherty
language : en
Publisher: Springer Science & Business Media
Release Date : 2011-12-18
Antibiotic Discovery And Development written by Thomas J. Dougherty and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011-12-18 with Medical categories.
This volume covers all aspects of the antibiotic discovery and development process through Phase II/III. The contributors, a group of highly experienced individuals in both academics and industry, include chapters on the need for new antibiotic compounds, strategies for screening for new antibiotics, sources of novel synthetic and natural antibiotics, discovery phases of lead development and optimization, and candidate compound nominations into development. Beyond discovery , the handbook will cover all of the studies to prepare for IND submission: Phase I (safety and dose ranging), progression to Phase II (efficacy), and Phase III (capturing desired initial indications). This book walks the reader through all aspects of the process, which has never been done before in a single reference. With the rise of antibiotic resistance and the increasing view that a crisis may be looming in infectious diseases, there are strong signs of renewed emphasis in antibiotic research. The purpose of the handbook is to offer a detailed overview of all aspects of the problem posed by antibiotic discovery and development.
Technological Challenges In Antibiotic Discovery And Development
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Author : National Research Council
language : en
Publisher: National Academies Press
Release Date : 2014-01-27
Technological Challenges In Antibiotic Discovery And Development written by National Research Council and has been published by National Academies Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-01-27 with Science categories.
Technological Challenges in Antibiotic Discovery and Development is the summary of a workshop convened by the Chemical Sciences Roundtable in September 2013 to explore the current state of antibiotic discovery and examine the technology available to facilitate development. Through formal presentations and panel discussions, participants from academia, industry, federal research agencies discussed the technical challenges present and the incentives and disincentives industry faces in antibiotic development, and identified novel approaches to antibiotic discovery. Antibiotic resistance is a serious and growing problem in modern medicine and it is emerging as a pre-eminent public health threat. Each year in the United States alone, at least two million acquire serious infections with bacteria that are resistant to one or more antibiotics, and at least 23,000 people die annually as a direct result of these antibiotic-resistant infections. In addition to the toll on human life, antibiotic-resistant infections add considerable and avoidable costs to the already overburdened U.S. health care system. This report explores the challenges in overcoming antibiotic resistance, screening for new antibiotics, and delivering them to the sites of infection in the body. The report also discusses a path forward to develop the next generation of potent antimicrobial compounds capable of once again tilting the battle against microbial pathogens in favor of humans. Technological Challenges in Antibiotic Discovery and Development gives a broad view of the landscape of antibiotic development and the technological challenges and barriers to be overcome.
Antibacterial Agents
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Author : Ranjith Kumavath
language : en
Publisher: BoD – Books on Demand
Release Date : 2017-05-31
Antibacterial Agents written by Ranjith Kumavath and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-05-31 with Science categories.
New drugs are frequently entering into the market along with the existing drugs. The antibacterial agents can be discussed in five major classes, i.e. classification based on the type of action, source, spectrum of activity, chemical structure and function. Resistance of bacteria to antibiotics is an urgent problem of the humanity, which leads us to the lack of therapy for serious bacterial infections. Development of new antibiotics has almost ceased in the last decades - even when a new antibiotic is launched, very soon the resistance of bacteria appears. Industrial textiles exposed as awnings, screens, tents; upholstery used in large public areas such as hospitals, hotels and stations; fabrics for transports; protective clothing and personal protective equipment; bed sheets and blankets; textiles left wet between processing steps; intimate apparel, underwear, socks and sportswear, disinfection of air and water for white rooms, hospitals and operating theatres, food and pharma industries, water depuration, drinkable water supplying and air conditioning systems. Many clinicians recommend alternative approaches to using antimicrobial substances. Moreover, the majority of bioagents demonstrate on antibiotics for treatment of a wide range of diseases in human sectors. However, the misuse and mishandling of drugs lead to microbial, particularly bacterial, resistance as well as result in the difficulty of treating microbial diseases. Hence, the proposed book will give more precise information on novel antibacterial compound(s).
Antimicrobial Chemotherapy
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Author : Roger Finch
language : en
Publisher: OUP Oxford
Release Date : 2012-01-05
Antimicrobial Chemotherapy written by Roger Finch and has been published by OUP Oxford this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-01-05 with Medical categories.
Antimicrobial agents are essential for the treatment of life-threatening infections and for managing the burden of minor infections in the community. In addition, they play a key role in organ and bone marrow transplantation, cancer chemotherapy, artificial joint and heart valve surgery. Unlike other classes of medicines, they are vulnerable to resistance from mutations in target microorganisms, and their adverse effects may extend to other patients (increased risk of cross-infection). As a consequence, there is a constant requirement for new agents, as well as practices that ensure the continued effective prescribing of licensed agents. Public awareness and concerns about drug resistant organisms has led to widespread publicity and political action in the UK, Europe and worldwide. The control of drug resistance and the implementation of good prescribing practice are now legal requirements in the UK as a result of the UK Health Act (2008). These fundamental changes underscore the need for a thorough understanding of the advantages and risks associated with specific antibiotic choices. This sixth edition of Antimicrobial Chemotherapy continues to be a valuable resource for undergraduates and graduates requiring a thorough grounding in the scientific basis and clinical application of these drugs. This new edition is updated to include the most recently licensed agents, notably in the treatment of viral infections including HIV/AIDS, and contains new guidance on prescribing practice and infection control practices that limit the development and spread of resistant organisms.
Antibiotics
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Author : Claudio O. Gualerzi
language : en
Publisher: John Wiley & Sons
Release Date : 2013-09-05
Antibiotics written by Claudio O. Gualerzi and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-09-05 with Medical categories.
Most of the antibiotics now in use have been discovered more or less by chance, and their mechanisms of action have only been elucidated after their discovery. To meet the medical need for next-generation antibiotics, a more rational approach to antibiotic development is clearly needed. Opening with a general introduction about antimicrobial drugs, their targets and the problem of antibiotic resistance, this reference systematically covers currently known antibiotic classes, their molecular mechanisms and the targets on which they act. Novel targets such as cell signaling networks, riboswitches and bacterial chaperones are covered here, alongside the latest information on the molecular mechanisms of current blockbuster antibiotics. With its broad overview of current and future antibacterial drug development, this unique reference is essential reading for anyone involved in the development and therapeutic application of novel antibiotics.
Combating Antimicrobial Resistance And Protecting The Miracle Of Modern Medicine
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Author : National Academies Of Sciences Engineeri
language : en
Publisher: National Academies Press
Release Date : 2022-07-20
Combating Antimicrobial Resistance And Protecting The Miracle Of Modern Medicine written by National Academies Of Sciences Engineeri and has been published by National Academies Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022-07-20 with Medical categories.
The National Strategy for Combating Antibiotic Resistant Bacteria, published in 2014, sets out a plan for government work to mitigate the emergence and spread of resistant bacteria. Direction on the implementation of this strategy is provided in five-year national action plans, the first covering 2015 to 2020, and the second covering 2020 to 2025. Combating Antimicrobial Resistance and Protecting the Miracle of Modern Medicine evaluates progress made against the national strategy. This report discusses ways to improve detection of resistant infections and estimate the risk to human health from environmental sources of resistance. In addition, the report considers the effect of agricultural practices on human and animal health and animal welfare and ways these practices could be improved, and advises on key drugs and diseases for which animal-specific test breakpoints are needed.