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Author: Miranda J Wallace Publisher: ISBN: Category : Languages : en Pages :
Book Description
Over the last century, the use of antibiotics has enabled many advances in modern medicine, making life as we know it possible. In recent years, however, emerging bacterial resistance to virtually all major antibiotic classes has resulted in a worldwide increase in morbidity, mortality, and financial burden associated with drug resistant infections. The antimicrobial resistance crisis presents an urgent need for new antimicrobials with distinct mechanisms of action from existing drugs. The current pharmaceutical pipeline of new antibiotics is limited due to three obstacles: a lack of understanding of resistance mechanisms, a dearth of novel mechanisms of action among new antibiotics, and drug discovery challenges unique to bacteria due to their cellular and physiological composition. My dissertation research addressed each of these challenges. The mechanisms of resistance to folate biosynthesis inhibitors in Staphylococcus aureus were explored from a genetic, biological, biochemical, and structural basis. Unexpected roles in resistance and fitness were attributed to various mutations in the sulfonamide target dihydropteroate synthase. This information currently guides the development of next-generation antifolates designed to avoid these characterized resistance strategies. In the subsequent chapter, a conditional metabolic screening approach was employed to discover inhibitors disrupting metabolic pathways related to folate biosynthesis. The testing conditions were optimized to measure the biological activity of antimetabolites, which is often masked by nutrients present in standard testing media. This screen yielded an inhibitor of cysteine synthase A in Escherichia coli, which was characterized in chapter four. Multiple experimental approaches yielded indications that the cysteine synthase A inhibitors have a false-product mechanism, resulting in a widespread impact on several key branches of metabolism beyond cysteine biosynthesis. The final research chapter describes the adaptation of the cellular thermal shift assay to explore target engagement in the Gram-negative cell system. Drug entry and accumulation are especially challenging to achieve in Gram-negative cells due to their unique dual membrane system and associated efflux machinery. This assay provided an early stage tool to quickly assess the ability of antimicrobial candidates to engage the intended target in the intact cell system and also measure efflux sensitivity. Taken together, this dissertation contributes to the fight against the antimicrobial resistance crisis from multiple angles, all within the context of bacterial metabolism which is a rich source of exciting new antibiotic targets.
Author: Miranda J Wallace Publisher: ISBN: Category : Languages : en Pages :
Book Description
Over the last century, the use of antibiotics has enabled many advances in modern medicine, making life as we know it possible. In recent years, however, emerging bacterial resistance to virtually all major antibiotic classes has resulted in a worldwide increase in morbidity, mortality, and financial burden associated with drug resistant infections. The antimicrobial resistance crisis presents an urgent need for new antimicrobials with distinct mechanisms of action from existing drugs. The current pharmaceutical pipeline of new antibiotics is limited due to three obstacles: a lack of understanding of resistance mechanisms, a dearth of novel mechanisms of action among new antibiotics, and drug discovery challenges unique to bacteria due to their cellular and physiological composition. My dissertation research addressed each of these challenges. The mechanisms of resistance to folate biosynthesis inhibitors in Staphylococcus aureus were explored from a genetic, biological, biochemical, and structural basis. Unexpected roles in resistance and fitness were attributed to various mutations in the sulfonamide target dihydropteroate synthase. This information currently guides the development of next-generation antifolates designed to avoid these characterized resistance strategies. In the subsequent chapter, a conditional metabolic screening approach was employed to discover inhibitors disrupting metabolic pathways related to folate biosynthesis. The testing conditions were optimized to measure the biological activity of antimetabolites, which is often masked by nutrients present in standard testing media. This screen yielded an inhibitor of cysteine synthase A in Escherichia coli, which was characterized in chapter four. Multiple experimental approaches yielded indications that the cysteine synthase A inhibitors have a false-product mechanism, resulting in a widespread impact on several key branches of metabolism beyond cysteine biosynthesis. The final research chapter describes the adaptation of the cellular thermal shift assay to explore target engagement in the Gram-negative cell system. Drug entry and accumulation are especially challenging to achieve in Gram-negative cells due to their unique dual membrane system and associated efflux machinery. This assay provided an early stage tool to quickly assess the ability of antimicrobial candidates to engage the intended target in the intact cell system and also measure efflux sensitivity. Taken together, this dissertation contributes to the fight against the antimicrobial resistance crisis from multiple angles, all within the context of bacterial metabolism which is a rich source of exciting new antibiotic targets.
Author: Prashant Kesharwani Publisher: Academic Press ISBN: 0128184817 Category : Medical Languages : en Pages : 434
Book Description
Drug Discovery Targeting Drug-Resistant Bacteria explores the status and possible future of developments in fighting drug-resistant bacteria. The book covers the majority of microbial diseases and the drugs targeting them. In addition, it discusses the potential targeting strategies and innovative approaches to address drug resistance. It brings together academic and industrial experts working on discovering and developing drugs targeting drug-resistant (DR) bacterial pathogens. New drugs active against drug-resistant pathogens are discussed, along with new strategies being used to discover molecules acting via new modes of action. In addition, alternative therapies such as peptides and phages are included. Pharmaceutical scientists, microbiologists, medical professionals, pathologists, researchers in the field of drug discovery, infectious diseases and microbial drug discovery both in academia and in industrial settings will find this book helpful. Written by scientists with extensive industrial experience in drug discovery Provides a balanced view of the field, including its challenges and future directions Includes a special chapter on the identification and development of drugs against pathogens which exhibit the potential to be used as weapons of war
Author: Rosaleen Anderson Publisher: John Wiley & Sons ISBN: 1118325443 Category : Science Languages : en Pages : 379
Book Description
Antibacterial agents act against bacterial infection either by killing the bacterium or by arresting its growth. They do this by targeting bacterial DNA and its associated processes, attacking bacterial metabolic processes including protein synthesis, or interfering with bacterial cell wall synthesis and function. Antibacterial Agents is an essential guide to this important class of chemotherapeutic drugs. Compounds are organised according to their target, which helps the reader understand the mechanism of action of these drugs and how resistance can arise. The book uses an integrated “lab-to-clinic” approach which covers drug discovery, source or synthesis, mode of action, mechanisms of resistance, clinical aspects (including links to current guidelines, significant drug interactions, cautions and contraindications), prodrugs and future improvements. Agents covered include: agents targeting DNA - quinolone, rifamycin, and nitroimidazole antibacterial agents agents targeting metabolic processes - sulfonamide antibacterial agents and trimethoprim agents targeting protein synthesis - aminoglycoside, macrolide and tetracycline antibiotics, chloramphenicol, and oxazolidinones agents targeting cell wall synthesis - β-Lactam and glycopeptide antibiotics, cycloserine, isonaizid, and daptomycin Antibacterial Agents will find a place on the bookshelves of students of pharmacy, pharmacology, pharmaceutical sciences, drug design/discovery, and medicinal chemistry, and as a bench reference for pharmacists and pharmaceutical researchers in academia and industry.
Author: Steven M. Firestine Publisher: Royal Society of Chemistry ISBN: 1782624244 Category : Medical Languages : en Pages : 289
Book Description
This book identifies and elaborates the most recent and compelling strategies for antibiotic drug discovery with a primary focus on new targets, mechanisms and molecular entities.
Author: Claudio O. Gualerzi Publisher: John Wiley & Sons ISBN: 3527659706 Category : Medical Languages : en Pages : 549
Book Description
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.
Author: National Research Council Publisher: National Academies Press ISBN: 0309180686 Category : Medical Languages : en Pages : 102
Book Description
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.
Author: Tony Romeo Publisher: Springer Science & Business Media ISBN: 3540754180 Category : Medical Languages : en Pages : 302
Book Description
Throughout the biological world, bacteria thrive predominantly in surface-attached, matrix-enclosed, multicellular communities or biofilms, as opposed to isolated planktonic cells. This choice of lifestyle is not trivial, as it involves major shifts in the use of genetic information and cellular energy, and has profound consequences for bacterial physiology and survival. Growth within a biofilm can thwart immune function and antibiotic therapy and thereby complicate the treatment of infectious diseases, especially chronic and foreign device-associated infections. Modern studies of many important biofilms have advanced well beyond the descriptive stage, and have begun to provide molecular details of the structural, biochemical, and genetic processes that drive biofilm formation and its dispersion. There is much diversity in the details of biofilm development among various species, but there are also commonalities. In most species, environmental and nutritional conditions greatly influence biofilm development. Similar kinds of adhesive molecules often promote biofilm formation in diverse species. Signaling and regulatory processes that drive biofilm development are often conserved, especially among related bacteria. Knowledge of such processes holds great promise for efforts to control biofilm growth and combat biofilm-associated infections. This volume focuses on the biology of biofilms that affect human disease, although it is by no means comprehensive. It opens with chapters that provide the reader with current perspectives on biofilm development, physiology, environmental, and regulatory effects, the role of quorum sensing, and resistance/phenotypic persistence to antimicrobial agents during biofilm growth.
Author: National Research Council Publisher: National Academies Press ISBN: 0309298172 Category : Science Languages : en Pages : 82
Book Description
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.
Author: Thomas J. Dougherty Publisher: Springer Science & Business Media ISBN: 1461414008 Category : Medical Languages : en Pages : 1119
Book Description
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.
Author: Miranda J Wallace
Author: Miranda J Wallace
Author: Prashant Kesharwani
Author: Rosaleen Anderson
Author: Gerry Wright
Author: Steven M. Firestine
Author: Claudio O. Gualerzi
Author: National Research Council
Author: Tony Romeo
Author: National Research Council
Author: Thomas J. Dougherty