A5046247522- Cancer therapeutics and mechanisms
- Carbohydrate Chemistry and Synthesis
- Antibiotics Pharmacokinetics and Efficacy
- Antibiotic Resistance in Bacteria
- Glycosylation and Glycoproteins Research
- Proteoglycans and glycosaminoglycans research
- Synthesis and Biological Evaluation
- Mitochondrial Function and Pathology
- Tuberculosis Research and Epidemiology
- Neutropenia and Cancer Infections
- Pancreatic function and diabetes
- Bioactive Compounds and Antitumor Agents
- Chemical Synthesis and Analysis
- Adipose Tissue and Metabolism
- Quinazolinone synthesis and applications
- Biochemical and Molecular Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Organic and Inorganic Chemical Reactions
- Antimicrobial Resistance in Staphylococcus
- Liver Disease Diagnosis and Treatment
- Diet, Metabolism, and Disease
- Synthesis and bioactivity of alkaloids
- Mycobacterium research and diagnosis
- Malaria Research and Control
- Trypanosoma species research and implications
University of Iowa
2014-2023
Fraternal Order of Eagles
2022-2023
VA Tennessee Valley Healthcare System
2014
University of Alabama at Birmingham
2013
Vanderbilt University
2013
Veterans Health Administration
2012
Wayne State University
2001-2002
Merck & Co., Inc., Rahway, NJ, USA (United States)
2000
Princeton University
1999-2000
Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt progression from multidrug-resistant extensively resistant disease; however, fluoroquinolone resistance is emerging new ways bypass required. To better explain known differences action, crystal structures WT Mtb gyrase cleavage core a fluoroquinolone-sensitized mutant were...
Vancomycin is an important drug for the treatment of Gram-positive bacterial infections. Resistance to vancomycin has begun appear, posing a serious public health threat. analogs containing modified carbohydrates are very active against resistant microorganisms. Results presented here show that these carbohydrate derivatives operate by different mechanism than vancomycin; moreover, peptide binding not required activity. It proposed carbohydrate-modified compounds effective bacteria because...
Although quinolones are the most commonly prescribed antibacterials, their use is threatened by an increasing prevalence of resistance. The common causes quinolone resistance mutations a specific serine or acidic residue in A subunit gyrase topoisomerase IV. These amino acids proposed to serve as critical enzyme-quinolone interaction site anchoring water-metal ion bridge that coordinates drug binding. To probe role bridge, we characterized wild-type, GrlA E85K , S81F/E85K E85A S81F/E85A and...
Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria a powerful approach to study treat these The triphenylphosphonium (TPP+) moiety the most widely used mitochondriotropic carrier. However, studies have shown that TPP+ not inert; conjugates uncouple mitochondrial oxidative phosphorylation. To date, all efforts toward addressing this problem focused on modifying lipophilicity TPP+-linker-cargo alter...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTADDITION / CORRECTIONThis article has been corrected. View the notice.Oxazolidinone Protected 2-Amino-2-deoxy-d-glucose Derivatives as Versatile Intermediates in Stereoselective Oligosaccharide Synthesis and Formation of α-Linked GlycosidesKamel Benakli, Congxiang Zha, Robert J. KernsView Author Information Department Pharmaceutical Sciences Wayne State University, Detroit, Michigan 48202 Cite this: Am. Chem. Soc. 2001, 123, 38,...
Significance Moxifloxacin and other fluoroquinolone antibacterial agents are important antituberculosis therapeutic agents. Fluoroquinolones kill Mycobacterium tuberculosis , the causative agent of tuberculosis, by increasing levels DNA breaks generated gyrase, an essential type II topoisomerase that regulates topology. As use in regimens is becoming more pronounced, understanding basis drug–gyrase interactions resistance important. By using a mechanism-based chemical biology approach, our...
Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing levels DNA cleavage mediated topoisomerase IV and gyrase. Quinolone resistance often associated with specific serine mutations in these enzymes. Therefore, determine basis for quinolone action resistance, we characterized wild-type B. anthracis IV, GrlA(S81F) GrlA(S81Y) quinolone-resistant mutants, effects...
Abstract Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs signaling in adipose, skeletal muscle, endothelium, secretion glycemic control. Here, we show that I Cl,SWELL protein are reduced adipose β-cells murine human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, functional studies, define a structure activity relationship to...
Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by increasing prevalence of target-mediated drug resistance. Greater than 90% mutations that confer quinolone resistance act disrupting enzyme–drug interactions coordinated a critical water–metal ion bridge. Quinazolinediones quinolone-like drugs but lack skeletal features necessary to support bridge interaction. These compounds clinical...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTThe Role of Hydrophobic Substituents in the Biological Activityof Glycopeptide AntibioticsRobert Kerns, Steven D. Dong, Seketsu Fukuzawa, Jeffrey Carbeck, Joyce Kohler, Lynn Silver, and Daniel KahneView Author Information Departments Chemistry Chemical Engineering Princeton University, Princeton, New Jersey 08544 Infectious Diseases, Merck Research Laboratories Rahway, 07065 Cite this: J. Am. Chem. Soc. 2000, 122, 50, 12608–12609Publication...
It is demonstrated that a ring-fused 2,3-oxazolidinone-protected derivative of 1-tolylthio-N-acetyl-d-glucosamine undergoes high-yield glycosidation under mild donor activation conditions. Stereoselective formation α-linked or β-linked glycosides dependent on reactivity acceptor alcohols, where rate correlates to stereochemical outcome. Evidence for the role glycosyl triflate intermediates and N-acetyl substituent 2N,3O-oxazolidinone ring in control presented.
Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety disease states. However, there is need understand the bioenergetic effects these agents and whether or not related redox properties, including their known pro-oxidant effects. We examined two mitochondrial-targeted CoQ in quinol forms, mitoquinol (MitoQ) plastoquinonyl-decyl-triphenylphosphonium (SkQ1), bovine aortic endothelial cells. used an extracellular oxygen proton...
Quinazolinediones (diones) are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV. To assess activity against mycobacteria, C-8-methoxy dione derivatives were compared with cognate fluoroquinolones by using cultured Mycobacterium smegmatis. Diones exhibited higher MIC values than fluoroquinolones; however, MICs for fluoroquinolone-resistant gyrA mutants, normalized to the wild-type cells, lower. Addition a 3-amino group 2,4-dione core increased relative while...
Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water–metal ion bridge most common quinolone mutations decrease by disrupting this bridge. As first step toward determining whether is general of quinolone–topoisomerase interaction, we characterized interactions...
Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug-topoisomerase-DNA in which DNA moiety is broken) with gyrase, one two bacterial targets drugs. Formation complexes, measured linearization a circular substrate, required...
We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed reducing intake. administered mitoQ or vehicle (ethanol) obesity-prone C57BL/6 mice fed high-fat (HF) normal-fat (NF) diets. MitoQ (500 <i>µ</i>M) was added drinking water for 28 weeks. significantly reduced total body mass fat in HF-fed but had no...
An agar-plate assay was adapted to examine aspects of quinolone structure that restrict the emergence quinolone-mediated resistance. When Escherichia coli applied agar containing nalidixic acid, number quinolone-resistant mutants arising during incubation decreased by raising drug concentration and mutations expected block induction SOS response (recA, lexA); mutant increased a mutator mutation (ung). The examination four related fluoroquinolones then revealed C-8 methoxy group an N-ethyl...
BackgroundOne way to address the growing problem of antimicrobial resistance is revive old compounds that may have intrinsic lethal activity obscured by protective factors. Bicyclomycin an inhibitor Rho transcription terminator itself shows little rapid activity. However, bicyclomycin participates in bacteriostatic synergy, which raises possibility conditions for synergy exist, perhaps through a suppression