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Drug Discovery Targeting Drug-Resistant Bacteria

Drug Discovery Targeting Drug-Resistant Bacteria
A Book

by Prashant Kesharwani,Sidharth Chopra,Arunava Dasgupta

  • Publisher : Academic Press
  • Release : 2020-05-15
  • Pages : 432
  • ISBN : 0128184817
  • Language : En, Es, Fr & De
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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

Discovering Antibacterial and Anti-resistance Agents Targeting Multi-drug Resistant ESKAPE Pathogens

Discovering Antibacterial and Anti-resistance Agents Targeting Multi-drug Resistant ESKAPE Pathogens
A Book

by Renee Marie Fleeman

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 138
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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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”.

Make Antibiotics Great Again: Combating Drug Resistance by Targeting LexA, a Regulator of Bacterial Evolution

Make Antibiotics Great Again: Combating Drug Resistance by Targeting LexA, a Regulator of Bacterial Evolution
A Book

by Charlie Y. Mo

  • Publisher : Unknown Publisher
  • Release : 2016
  • Pages : 274
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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The ability of bacterial pathogens to evolve and adapt to our antimicrobial agents has precipitated a global health crisis where treatment options for bacterial infections are running low. Recently, studies have shown that the ability to acquire resistance is linked to the SOS response, which is a widely conserved network of genes involved in both high fidelity and error-prone DNA damage repair. The SOS response is regulated by the DNA-binding protein, RecA, and a repressor-protease, LexA. When the cell experiences stress, which can be caused by antibiotics, RecA polymerizes along single-stranded DNA and thereby stimulates LexA to undergo a conformational change and self-cleavage reaction (autoproteolysis). LexA self-cleavage de-represses downstream SOS genes, which are involved in both stress tolerance and mutagenesis. Various studies have shown that inactivating LexA autoproteolysis can both reduce the viability of bacteria under antibiotic stress and impede their ability to acquire resistance. These results therefore suggest that targeting LexA therapeutically could offer a novel way to combat the rise of resistance in pathogens, although to date no LexA inhibitors have been found. To facilitate the development of such therapeutics, we focused our efforts on examining LexA from 1) biochemical, 2) microbiological, and 3) drug discovery perspectives. On the biochemical front, we elucidated the substrate preference of LexA’s serine protease active site to form a better understanding of the target enzyme’s active site architecture. Performing saturation mutagenesis on the LexA’s internal cleavage loop, we showed that LexA possesses a unique active site, revealing residues involved in specific molecular recognition and conformational change. On the microbiological front, we examined how different LexA activities can impact bacterial drug susceptibility and stress-induced mutagenesis. Employing engineered E. coli strains with a spectrum of SOS activities, we showed that modulating LexA activity can increase bacterial susceptibility to antibiotics, while also tuning stress-induced mutagenesis. Finally, on the drug discovery front, we designed a high-throughput screen that enabled us to discover small molecule inhibitors of the LexA/RecA axis in collaboration with GlaxoSmithKline. Together, this work provides a multi-pronged foray into developing therapeutics that target the SOS pathway and combat the rise of antibiotic resistance.

Discovery and Development of Antimicrobial Agents Targeting Multi-drug Resistant Bacterial, Fungal, and Parasitic Pathogens

Discovery and Development of Antimicrobial Agents Targeting Multi-drug Resistant Bacterial, Fungal, and Parasitic Pathogens
From the Bench to the Bedside

by Danielle N. Turner

  • Publisher : Unknown Publisher
  • Release : 2019
  • Pages : 382
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Preclinical Antimicrobial Drug Discovery

Preclinical Antimicrobial Drug Discovery
Development and Evaluation of a Platform for High-throughput Screening in Vitro and an Immunocompromised Animal Model

by Bill Lee

  • Publisher : Unknown Publisher
  • Release : 2006
  • Pages : 254
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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"The incidence of infections caused by antibiotic-resistant bacteria and fungi is rising rapidly. Once considered as little more than a nuisance, antibiotic resistance has become a serious threat. The mortality rate for some infections is approaching that of the pre-antibiotic era. New antimicrobials are needed urgently. Prior to the introduction of any new antimicrobial, comprehensive toxicity and efficacy profiles are assessed in preclinical studies. This thesis focuses on two key stages of preclinical antimicrobial drug development, specifically compound screening in vitro and animal efficacy testing in vivo. We developed a sensitive colorimetric platform with high-throughput capacity for the rapid screening of candidate antimicrobials. This platform could be adapted to assess compounds targeting a range of bacteria, fungi (such as Candida albicans), and protozoan parasites (such as Leishmania major). When this assay was modified to measure minimum inhibitory concentrations (MICs) for bacteria, 100% agreement within one dilution was achieved compared to the gold-standard method. A novel antifungal compound was taken forward to animal testing in an immunocompromised mouse model. We demonstrated herein that a histone deacetylase inhibitor in combination with an imidazole can synergise to produce a potent antifungal effect. A dose-dependent response, defined as a lower fungal burden and a higher survival rate, was achieved with increasing concentrations of the novel inhibitor." --

Frontiers in Clinical Drug Research - Anti Infectives: Volume 5

Frontiers in Clinical Drug Research - Anti Infectives: Volume 5
A Book

by Atta-ur-Rahman

  • Publisher : Bentham Science Publishers
  • Release : 2019-06-11
  • Pages : 246
  • ISBN : 1681086387
  • Language : En, Es, Fr & De
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Frontiers in Clinical Drug Research – Anti infectives is a book series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of infectious diseases. The scope of the book series covers a range of topics including the chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of infectious diseases. Reviews in this series also include research on multi drug resistance and pre-clinical / clinical findings on novel antibiotics, vaccines, antifungal agents and antitubercular agents.Frontiers in Clinical Drug Research – Anti infectives is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of anti infective drug discovery and epidemiology. The fifth volume of this series features six reviews: - Integrated Approaches for Marine Actinomycete Biodiscovery - Therapeutic Use of Commensal Microbes: Fecal/Gut Microbiota Transplantation - Alternative Approaches to Antimicrobials - Nanoantibiotics: Recent Developments and Future - Cranberry Juice and Other Functional Foods in Urinary Tract Infections in Women: A Review of Actual Evidence and Main Challenges - Targeting Magnesium Homeostasis as Potential Anti-Infective Strategy Against Mycobacteria

Frontiers in Anti-Infective Drug Discovery

Frontiers in Anti-Infective Drug Discovery
A Book

by Atta-ur-Rahman,M. Iqbal Choudhary

  • Publisher : Bentham Science Publishers
  • Release : 2015-06-30
  • Pages : 230
  • ISBN : 1681080826
  • Language : En, Es, Fr & De
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This eBook series brings updated reviews to readers interested in advances in the development of anti-infective drug design and discovery. The scope of the eBook series covers a range of topics including rational drug design and drug discovery, medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. Frontiers in Anti-Infective Drug Discovery is a valuable resource for pharmaceutical scientists and post-graduate students seeking updated and critically important information for developing clinical trials and devising research plans in this field. The fourth volume of this series features 5 chapters that cover the following topics: - An overview of the incidence of neuraminadase resistance in influenza viruses in the Americas from 2004 to 2014 - Phenothiazines and derivative compounds for treating Trypanosoma cruzi infections - New antibacterial drug targets such as polysaccharide deacetylases - Improvements in aminoglycoside synthesis and biological activity (including RNA targeting) - A review of new chemotherapeutic agents against common infections.

Chemical Biology Approaches Towards Cell-permeable Inhibitors Targeting Nonribosomal Peptide Biosynthesis

Chemical Biology Approaches Towards Cell-permeable Inhibitors Targeting Nonribosomal Peptide Biosynthesis
A Book

by Tony Dwayne Davis,Cornell University. Weill Cornell Graduate School of Medical Sciences

  • Publisher : Unknown Publisher
  • Release : 2014
  • Pages : 328
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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The emergence of drug-resistant bacteria presents opportunities to develop novel antibacterials that address this area of urgent medical need. Recently, numerous groups have developed potent small-molecule inhibitors targeting essential bacterial adenylation enzymes. However, one factor that hinders the further development of these compounds as potential antibacterials is their lack of cellular activity, presumably due to poor cellular permeability. The permeability of small molecules in bacteria remains elusive and efforts to understand permeability would greatly facilitate future drug discovery efforts in this arena. Herein, we address bacterial permeability on two major fronts. In the first half of this dissertation, we discuss progress towards the design and synthesis of cell-permeable small molecules targeting amino acid adenylation domains that are implicated in the biosynthesis of bacterial siderophores. We employed isosteric replacement and prodrug design to improve cellular permeability. In the second half of this dissertation, we develop a systematic and quantitative platform to understand bacterial small-molecule permeability. We evaluate the accumulation and efflux of a panel of ten structurally-related compounds in three bacteria with cell envelopes of varying complexities. Then, we use cheminformatic analyses to find correlations between structural and physicochemical properties, accumulation, and efflux sensitivity.

Dissemination, Suppression, and Evolution of Antibiotic Resistance in Human Pathogens

Dissemination, Suppression, and Evolution of Antibiotic Resistance in Human Pathogens
A Book

by Patrick Rolland Gonzales

  • Publisher : Unknown Publisher
  • Release : 2015
  • Pages : 152
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Multidrug-resistant (MDR) human pathogens represent a growing threat to human health. This threat is compounded by dissemination of antibiotic resistance genes from diverse microbial reservoirs. The selection of current antibiotic drugs that can clear bacterial infections with minimal human side effects is limited, and bacteria can rapidly evolve or acquire new resistance to these drugs on the order of weeks. Compounding this issue is the existence of an "innovation gap", where drug-discovery efforts of pharmaceutical companies to screen massive libraries of natural and synthetic compounds have reached practical limits. Concurrently with drug-discovery, synthetic tailoring methods with existing drug scaffolds, cycling of existing drugs to exploit collateral sensitivity, and lower-order combination therapies have slowed, but not stopped this rise. These strategies have, in the past, been successfully employed against the major MDR Gram-negative and Gram-positive human isolates, also known as ESKAPE pathogens, comprised of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and ESBL-producing Enterobacteriaceae species. These six ESKAPE strains are collectively responsible for a substantial percentage of nosocomial infections in the modern hospital and represent the vast majority of isolates whose increasing resistance to antibiotic agents presents serious therapeutic dilemmas for physicians, not to mention the considerable economic and social burdens placed. Attenuating this increase in multidrug resistance is crucial, as the pipeline of novel antibiotic compounds is rapidly drying up. In this work, I explore three aspects of antibiotic resistance, with particular focus on multidrug-resistant (MDR) human pathogens: 1) how antibiotic resistance genes have been disseminated in the clinic and the environment by Pseudomonas aeruginosa, a bacterial strain that can serve as a reservoir and vector of antibiotic resistance; 2) how existing antibiotic drugs can be combined to generate increased potency through synergy, and can also suppress the emergence of higher resistance in MRSA through collateral sensitivities of the components; and 3) how a novel bifunctional antibiotic resistance enzyme, AAC(6')-Ib-cr, can overcome fitness costs incurred by its acquired resistance function against ciprofloxacin, through mutational analysis of its variants in a diverse genomic library. We determined that the pseudomonads isolated from the clinical niche library were significantly enriched for all resistance gene functions in general, and all beta-lactamases in particular. Strikingly, these resistance genes were found on contigs with collinear resistance genes conferring resistance to multiple drug classes, and adjacent to mobilizable genomic elements like transposons and integrons. Also notable, many of the resistance genes have highest nucleotide and amino-acid identity to non-Pseudomonas species, indicating signatures of recent horizontal gene transfer (HGT). Collectively, these findings strongly suggest Pseudomonas aeruginosa to be a reservoir species and possible vector for the further dissemination of mobilizable antibiotic resistance genes. We identified multiple triple combinations of antibiotics with high synergy against P. aeruginosa DK2. This was not unexpected in this case, as prior work suggested that drugs targeting maximally orthogonal systems in bacteria would increase the likelihood of inducing a fragile state, where the bacterium is no longer capable of performing basic metabolic functions and is killed. In contrast to orthogonal drug components composing maximally synergistic combinations in Pseudomonas, we identified a new potential therapy against MRSA N315 consisting of a combination of clinically approved drugs from three distinct generations and subclasses of [beta]-lactam antibiotics, all targeting cell-wall synthesis: meropenem, piperacillin, and tazobactam (ME/PI/TZ). Because MRSA strains are highly resistant to most beta-lactam drugs, the remarkable synergy present in this triple combination was unexpected, and we found the synergy to derive from the differential targeting of multiple constituents of the cell wall synthesis system in MRSA, especially the allosteric triggering of the PBP2a enzyme by meropenem to open the active site for inhibition by the beta-lactams in the combination. The efficacy of the ME/PI/TZ combination in completely clearing aggressive MRSA infection in mice was also unexpected, as use of beta-lactams is not currently suggested for treating MRSA in the clinic because of the resistance conferred against beta-lactams given singly by the PBP2a enzyme. After generating libraries of barcoded, wild-type and mutant variants of the aac(6')-Ib-cr gene in an E. coli host, and exposing the libraries to high concentrations of kanamycin and ciprofloxacin, we found several clones that displayed increases in fitness toward both kanamycin and ciprofloxacin, thus refuting our hypothesis of increases in fitness toward one drug being anti-correlated with fitness to the other. However, we successfully generated libraries of the aac(6')-Ib-cr gene with unique barcodes for each clone and with endogenous ribosome binding sites for proper expression of the gene variants under arabinose-inducible expression in plasmid pBAD24. Initial high-throughput sequencing runs of libraries with MiSeq were of low efficiency, likely due to the large size of the gene construct and necessary adapter sequences for hybridization to the Illumina flow cells. Our attempts to subclone the construct, in order to generate sub-libraries more amenable to high-throughput sequencing with MiSeq, were unsuccessful. But, we successfully generated circularized aac(6')-Ib-cr constructs, bringing the necessary F and R barcodes in close proximity for short, direct sequencing with MiSeq. In sum, we have surveyed the dissemination of antibiotic resistance across global ecological niches in Pseudomonas aeruginosa, which we may consider a reservoir and vector of antibiotic resistance genes. We have sought out new ways to treat highly MDR human pathogens and discovered triple antibiotic drug combinations that are highly synergistic against Pseudomonas and MRSA strains, and especially an unexpected triple combination of beta-lactam drugs that strongly synergize to confer high potency against MRSA infections in vitro and in vivo, and also suppress emergence of higher antibiotic resistance through reciprocal collateral sensitivities of the components. Finally, we have focused on the potential of one novel gene conferring bifunctional resistance against aminoglycoside and fluoroquinolone antibiotics, aac(6')-Ib-cr, to assess whether this gene can acquire more mutations to become even more robust at resisting these drug classes in the clinic.

Antibacterial Agents

Antibacterial Agents
Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications

by Rosaleen Anderson,Paul W. Groundwater,Adam Todd,Alan Worsley

  • Publisher : John Wiley & Sons
  • Release : 2012-05-30
  • Pages : 376
  • ISBN : 1118325443
  • Language : En, Es, Fr & De
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Antibacterial agents act against bacterial infection either bykilling the bacterium or by arresting its growth. They do this bytargeting bacterial DNA and its associated processes, attackingbacterial metabolic processes including protein synthesis, orinterfering with bacterial cell wall synthesis and function. Antibacterial Agents is an essential guide to this importantclass of chemotherapeutic drugs. Compounds are organised accordingto their target, which helps the reader understand the mechanism ofaction of these drugs and how resistance can arise. The book usesan integrated “lab-to-clinic” approach which coversdrug discovery, source or synthesis, mode of action, mechanisms ofresistance, clinical aspects (including links to currentguidelines, significant drug interactions, cautions andcontraindications), prodrugs and future improvements. Agents covered include: agents targeting DNA - quinolone, rifamycin, and nitroimidazoleantibacterial agents agents targeting metabolic processes - sulfonamideantibacterial agents and trimethoprim agents targeting protein synthesis - aminoglycoside, macrolideand tetracycline antibiotics, chloramphenicol, andoxazolidinones agents targeting cell wall synthesis - β-Lactam andglycopeptide antibiotics, cycloserine, isonaizid, anddaptomycin Antibacterial Agents will find a place on the bookshelvesof students of pharmacy, pharmacology, pharmaceutical sciences,drug design/discovery, and medicinal chemistry, and as a benchreference for pharmacists and pharmaceutical researchers inacademia and industry.

Sustainable Agriculture Reviews 46

Sustainable Agriculture Reviews 46
Mitigation of Antimicrobial Resistance Vol 1 Tools and Targets

by Harsh Panwar,Chetan Sharma,Eric Lichtfouse

  • Publisher : Springer Nature
  • Release : 2020-09-29
  • Pages : 231
  • ISBN : 3030530248
  • Language : En, Es, Fr & De
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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.

Model Organisms for Microbial Pathogenesis, Biofilm Formation and Antimicrobial Drug Discovery

Model Organisms for Microbial Pathogenesis, Biofilm Formation and Antimicrobial Drug Discovery
A Book

by Busi Siddhardha,Madhu Dyavaiah,Asad Syed

  • Publisher : Springer Nature
  • Release : 2020-03-28
  • Pages : 684
  • ISBN : 9811516952
  • Language : En, Es, Fr & De
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This book provides essential insights into microbial pathogenesis, host-pathogen interactions, and the anti-microbial drug resistance of various human pathogens on the basis of various model organisms. The initial sections of the book introduce readers to the mechanisms of microbial pathogenesis, host-pathogen interactions, anti-microbial drug resistance, and the dynamics of biofilm formation. Due to the emergence of various microbial resistant strains, it is especially important to understand the prognosis for microbial infections, disease progression profiles, and mechanisms of resistance to antibiotic therapy in order to develop novel therapeutic strategies. In turn, the second part of the book presents a comparative analysis of various animal models to help readers understand microbial pathogenesis, host-pathogen interactions, anti-microbial drug discovery, anti-biofilm therapeutics, and treatment regimes. Given its scope, the book represents a valuable asset for microbiologists, biotechnologists, medical professionals, drug development researchers, and pharmacologists alike.

Antimicrobial Peptides

Antimicrobial Peptides
Challenges and Future Perspectives

by K. Ajesh,K. Sreejith

  • Publisher : Academic Press
  • Release : 2022-03-15
  • Pages : 266
  • ISBN : 9780323856829
  • Language : En, Es, Fr & De
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Antimicrobial Peptides: Discovery to Drug Development covers the latest developments about antimicrobial peptides in the scenario of drug resistance. The book is divided in to 16 chapters that are arranged in a sequence and preceded by chapters on historical developments and role as regulatory molecules in innate defense mechanism. Emphasis is given to purification techniques and characterization in detail suitable for interdisciplinary research. Chapters from 5 to 10 provide an inventory of various antimicrobial peptides, from a diverse array of organisms such as bacteria, fungi, insects, amphibians, plants and mammals. The marine ecosystem being one of the excellent sources of unexplored peptides, chapter 11 broadens readers understanding on marine based antimicrobial peptides. This is followed by an informative overview on peptides with antiviral properties and those targeting multi drug resistant bacteria. Additionally, recent reports and mechanism on resistance against antimicrobial peptides are provided. Key insights in to challenges and future perspectives of peptide drug development have been extensively covered in the end chapters. Antimicrobial Peptides: Discovery to Drug Development is an invaluable reference and essential reading for bioscience students, researchers and industrialists. Emphasizes antimicrobial peptides targeting various human viruses and multidrug resistant bacteria Written by internationally recognized experts that provide the readers with a wide and useful perspective of the chapters listed Provides in-depth resources for undertaking a research work in antimicrobial peptides with the inclusion of chapters on purification techniques and structural details Addresses the possibility and availability of peptide antibiotics in the global drug market against the conventional antibiotics Serves as a complete resource from the discovery to drug development of peptide antibiotics

Antimicrobials—Advances in Research and Application: 2012 Edition

Antimicrobials—Advances in Research and Application: 2012 Edition
A Book

by Anonim

  • Publisher : ScholarlyEditions
  • Release : 2012-12-26
  • Pages : 464
  • ISBN : 146499305X
  • Language : En, Es, Fr & De
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Antimicrobials—Advances in Research and Application: 2012 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Antimicrobials. The editors have built Antimicrobials—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Antimicrobials in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Antimicrobials—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.

Discovery and Characterization of the Antibacterial Activity of Small Molecules

Discovery and Characterization of the Antibacterial Activity of Small Molecules
A Book

by Katherine Ann Hurley

  • Publisher : Unknown Publisher
  • Release : 2016
  • Pages : 558
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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The discovery of antibiotics had an enormous impact on medicine because it revolutionized medical procedures and prolonged the life expectancy of patients. The unrestricted, yet indispensable, use of antibiotics in clinics has led to the accumulation of infections associated with drug resistant strains of bacteria. The majority of the antibiotics that are commonly utilized were discovered during the 'golden age' — the 1940s to 1960s — of antibacterial discovery. Unfortunately, no new classes of antibiotics have been discovered in 29 years. The prevalence of antibiotic resistant bacteria and the lack of discovery have produced a difficult situation that necessitates global attention and collaborative action. In this thesis, we describe our contribution to filling the antibacterial discovery void. We illustrate several discovery strategies used in antibiotic research and explain experimental characterization challenges in the context of identifying inhibitors of the cytoskeletal protein, FtsZ. We describe the mechanism of action and new potent analogs of a new class of narrow spectrum DNA gyrase inhibitors. We characterize a new class of broad-spectrum membrane-targeting small molecules with a unique phenotype using a structure-activity relationship study and cell imaging studies. Finally, we identified another class of membrane-targeting small molecules, which demonstrate potential as antibiotic adjuvants against clinically relevant gram-negative and gram-positive bacteria. These projects have provided promising small molecules with antibacterial activity and therapeutic potential as antibiotics.

Development and Applications of the Hint Forcefield in Prediction of Antibiotic Efflux and Virtual Screening for Antivirals

Development and Applications of the Hint Forcefield in Prediction of Antibiotic Efflux and Virtual Screening for Antivirals
A Book

by Aurijit Sarkar

  • Publisher : Unknown Publisher
  • Release : 2010
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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This work was aimed at developing novel tools that utilize HINT, an empirical forcefield capable of quantitating both hydrophobic and hydrophilic (hydropathic) interactions, for implementation in theoretical biology and drug discovery/design. The role of hydrophobicity in determination of macromolecular structure and formation of complexes in biological molecules is undeniable and has been the subject of research across several decades. Hydrophobicity is introduced, with a review of its history and contemporary theories. This is followed by a description of various methods that quantify this all-pervading phenomenon and their use in protein folding and contemporary drug design projects - including a detailed overview of the HINT forcefield. The specific aim of this dissertation is to introduce our attempts at developing new methods for use in the study of antibacterial drug resistance and antiviral drug discovery. Multidrug efflux is commonly regarded as a fast growing problem in the field of medicine. Several species of microbes are known to have developed resistance against almost all classes of antibiotics by various modes-of-action, which include multidrug transporters (a.k.a. efflux pumps). These proteins are present in both gram-positive and gram-negative bacteria and extrude molecules of various classes. They protect the efflux pump-expressing bacterium from harmful effects of exogenous agents by simply evacuating the latter. Perhaps the best characterized mechanism amongst these is that of the AcrA-AcrB-TolC efflux pump. Data is available in literature and perhaps also in proprietary databases available with pharmaceutical companies, characterizing this pump in terms of the minimum inhibitory concentration ratios (MIC ratios) for various antibiotics. We procured a curated dataset of 32 [beta]-lactam and 12 antibiotics of other classes from this literature. Initial attempts at studying the MIC ratios of [beta]-lactam antibiotics as a function of their three dimensional topology via 3D-quantitative structure activity relationship (3D-QSAR) technology yielded seemingly good models. However, this methodology is essentially designed to address single receptor-ligand interactions. Molecules being transported by the efflux pump must undoubtedly be involved in multiple interactions with the same. Notably, such methods require a pharmacophoric overlap of ligands prior to the generation of models, thereby limiting their applicability to a set of structurally-related compounds. Thus, we designed a novel method that takes various interactions between antibiotic agents and the AcrA-AcrB-TolC pump into account in conjunction with certain properties of the drugs. This method yielded mathematical models that are capable of predicting high/low efflux with significant efficiency ([greater than] 93% correct). The development of this method, along with the results from its validation, is presented herein. A parallel aim being pursued by us is to discover inhibitors for hemagglutinin-neuraminidase (HN) of human parainfluenza virus type 3 (HPIV3) by in silico screening. The basis for targeting HN is explored, along with commentary on the methodology adopted during this effort. This project yielded a moderate success rate of 34%, perhaps due to problems in the computational methodology utilized. We highlight one particular problem - that of emulating target flexibility - and explore new avenues for overcoming this obstacle in the long run. As a starting point towards enhancing the tools available to us for virtual screening in general (and for discovering antiviral compounds in specific), we explored the compatibility between sidechain rotamer libraries and the HINT scoring function. A new algorithm was designed to optimize amino acid residue sidechains, if provided with the backbone coordinates, by generating sidechain positions using the Dunbrack and Cohen backbone-dependent rotamer library and scoring them with the HINT scoring function. This rotamer library was previously used by its developers previously to design a very successful sidechain optimization algorithm called SCWRL. Output structures from our algorithm were compared with those from SCWRL and showed extraordinary similarities as well as significant differences, which are discussed herein. This successful implementation of HINT in our sidechain optimization algorithm establishes the compatibility between this forcefield and sidechain rotamer libraries. Future aims in this project include enhancement of our current algorithm and the design of a new algorithm to explore partial induced-fit in targets aimed at improving current docking methodology. This work shows significant progress towards the implementation of our hydropathic force field in theoretical modeling of biological systems in order to enhance our ability to understand atomistic details of inter - and intramolecular interactions which must form the basis for a wide variety of biological phenomena. Such efforts are key to not only to understanding the said phenomena, but also towards a solid basis for efficient drug design in the future.

A Novel Approach to the Discovery of Natural Products from Actinobacteria

A Novel Approach to the Discovery of Natural Products from Actinobacteria
A Book

by Rahmy Tawfik

  • Publisher : Unknown Publisher
  • Release : 2017
  • Pages : 136
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Actinobacteria, primarily the genus Streptomyces, have led to the development of a number of antibiotics, which result from their secondary metabolites or modified derivatives. Secondary metabolite production can result from competition with neighboring microbes in an effort to disrupt growth, aiding in the competition for vital nutrients in impoverished conditions. Such secondary metabolites have the potential to affect a plethora of cellular functions in target cells, including, cell wall development, protein synthesis, protein function and fatty acid synthesis/metabolism. Due to the pandemic spread of antibiotic resistant bacteria, it is imperative to continue the search for new therapeutic agents targeting these deadly organisms. As such, our group explored soil and marine samples from Tampa Bays surrounding farmlands and waterways for secondary metabolite producing microbes using culture methods specific to Actinobacteria. Through these efforts we isolated over 750 bacterial species, of which almost half are confirmed Actinobacteria. In an attempt to derive new and novel chemistry from these organisms, we used our novel collection, and developed techniques for epigenetic modification to un-silence dormant and cryptic metabolic pathways. Our work reveals that a number of these Actinobacteria produce secondary metabolites that are effective against the ESKAPE pathogens, some at very low concentrations. Although the bioactivity from secondary metabolites is a well-known source for antibiotic drug discovery, our epigenetic methods suggest a potential to isolate previously overlooked compounds that have a very real possibility for use as antibacterial therapeutics.

Frontiers in Clinical Drug Research - Anti Infectives: Volume 4

Frontiers in Clinical Drug Research - Anti Infectives: Volume 4
A Book

by Atta-ur- Rahman

  • Publisher : Bentham Science Publishers
  • Release : 2017-11-02
  • Pages : 275
  • ISBN : 1681084872
  • Language : En, Es, Fr & De
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Frontiers in Clinical Drug Research – Anti infectives is an eBook series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of infectious diseases. The scope of the eBook series covers a range of topics including the chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of infectious diseases. Reviews in this series also include research on multi drug resistance and pre-clinical / clinical findings on novel antibiotics, vaccines, antifungal agents and antitubercular agents. Frontiers in Clinical Drug Research – Anti infectives is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of anti infective drug discovery and epidemiology. The fourth volume of this series features reviews that cover a variety of topics including: -Strategies to prolong antibiotic life -Catalytic antibodies for targeting rabies and influenza viruses -Antiviral therapies for arenaviruses -The role of steroids in viral infections -Monoclonal antibody manufacturing processes -Prevention and eradication of biofilms in medical devices

Antibacterial Agents

Antibacterial Agents
Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications

by Rosaleen Anderson,Paul W. Groundwater,Adam Todd,Alan Worsley

  • Publisher : Wiley
  • Release : 2012-07-23
  • Pages : 378
  • ISBN : 9780470972458
  • Language : En, Es, Fr & De
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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.

Antibacterial Agents

Antibacterial Agents
Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications

by Rosaleen Anderson,Paul W. Groundwater,Adam Todd,Alan Worsley

  • Publisher : Wiley
  • Release : 2012-07-23
  • Pages : 378
  • ISBN : 9780470972441
  • Language : En, Es, Fr & De
GET BOOK

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.