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

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

This book compiles the latest information in the field of antibacterial discovery, especially with regard to the looming threat of multi-drug resistance. The respective chapters highlight the discovery of new antibacterial and anti-infective compounds derived from microbes, plants, and other natural sources. The potential applications of nanotechnology to the fields of antibacterial discovery and drug delivery are also discussed, and one section of the book is dedicated to the use of computational tools and metagenomics in antibiotic drug discovery. Techniques for efficient drug delivery are also covered. The book provides a comprehensive overview of the progress made in both antibacterial discovery and delivery, making it a valuable resource for academic researchers, as well as those working in the pharmaceutical industry.

According to the World Health Organization, antimicrobial resistance is a major threat to global health because the number of alternative antibiotics is very limited. Antimicrobial resistance is a slow evolutionary process that has been accelerated by human activities in health, environment and agriculture sectors. Due to their wide application, antibiotics and their residues have been found in almost all food products and natural ecosystems. This book reviews the drivers, impact and mitigation of antimicrobial resistance, with focus on methods and targets.

Antibiotic resistance has been a developing problem for mankind in recent decades and multi-drug resistant bacteria are now encountered that are resistant to all treatment options available. In 2014, the World Health Organization announced that this problem is driving us towards a “post-antibiotic era” that will change the face of modern medicine as we know it. If lack of novel antibiotic development and FDA approval continues, by the year 2050, 10 million people will die each year to an antimicrobial resistant bacterial infection. With lack of pharmaceutical industry involvement in developing novel antibiotics, the responsibility now lies within the academic institutions to identify potential novel therapeutics to fuel the antibiotic drug discovery pipeline. Combinatorial chemistry is one technique used to expedite the discovery process by assessing a large chemical space in a relatively short time when compared to traditional screening approaches. Combinatorial libraries can be screened using multiple approaches and has shown successful application towards many disease states. We initially discovered broad spectrum antibacterial bis-cyclic guanidines using combinatorial libraries and expanded on the knowledge of the physiochemical attributes necessary to inhibit Gram negative bacterial pathogens. Following this success, we continued to assess the combinatorial libraries for adjunctive therapeutics that potentiate the activity of obsolete clinical antibiotics. The polyamine efflux pump inhibitors discovered in this subsequent study prove the benefits of using the large chemical space provided in the combinatorial libraries to identify a variety of therapeutics. Our studies always begin with identifying an active compound and active compounds undergo hit-to-lead optimization. This optimization studies are of utmost importance in developing a novel antibacterial agent for therapeutic applications. Our medicinal chemistry work described here is proof of the success of careful structure activity analyses to optimize a hit scaffold to create a more effective antibacterial agent. Overall, our work described here reveals the potential role of academic institutions in fending off the impending “post-antibiotic era”.

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.

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.