A5069663695- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Inflammasome and immune disorders
- Eicosanoids and Hypertension Pharmacology
- Heme Oxygenase-1 and Carbon Monoxide
- Microbial Natural Products and Biosynthesis
- ATP Synthase and ATPases Research
- Enzyme Structure and Function
- Antibiotic Resistance in Bacteria
- Computational Drug Discovery Methods
- Cancer therapeutics and mechanisms
- Immune Response and Inflammation
- Phenothiazines and Benzothiazines Synthesis and Activities
- Biochemical and Molecular Research
- Macrophage Migration Inhibitory Factor
University of North Carolina at Chapel Hill
2024
Infectious Disease Research Institute
2017-2019
Seattle University
2019
The imidazopyridines are a promising new class of antitubercular agents with potent activity in vitro and vivo We isolated mutants Mycobacterium tuberculosis resistant to representative imidazopyridine; the had large shifts (>20-fold) MIC. Whole-genome sequencing revealed mutations Rv1339, hypothetical protein unknown function. three further compounds from series; two single nucleotide polymorphisms Rv1339 third compound QcrB, proposed target for series. All strains were compounds,...
With the emergence of multidrug-resistant strains Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms action. Herein, we describe identification morpholino-thiophenes (MOT) series following phenotypic screening Eli Lilly corporate library against M. strain H37Rv. The design, synthesis, and structure-activity relationships range analogues around confirmed actives are described. Optimized leads potent whole cell activity H37Rv, no cytotoxicity flags, in...
The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a central regulator of innate immunity, essential for processing and release interleukin-1<i>β</i> pyroptotic cell death. As endogenous NLRP3 activating triggers are hallmarks many human chronic inflammatory diseases, inhibition has emerged as therapeutic target. Here we identify NDT-19795 novel carboxylic acid-containing activation inhibitor in both mouse monocytes macrophages. Remarkably, conversion the...
Azoles are a class of antimicrobial drugs used clinically to treat yeast and fungal infections. Against pathogenic fungi, azoles act by inhibiting the activity cytochrome P450 Cyp51, which is involved in synthesis critical component cell membrane. have antibacterial activity, including against mycobacteria, but basis for this not well-understood. We demonstrated that imidazoles bactericidal Mycobacterium tuberculosis. A marked increase reactive oxygen species (ROS) was observed within...
Interleukin (IL)-1β is an apex proinflammatory cytokine produced in response to tissue injury and infection. The output of IL-1β from monocytes macrophages regulated not only by transcription translation but also post-translationally. Release the active requires activation inflammasomes, which couple post-translational proteolysis with pyroptosis. Among inflammasome platforms, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) implicated pathogenesis numerous human disorders...
Tuberculosis is a massive global burden and Mycobacterium tuberculosis increasingly resistant to first- second-line drugs. There an acute need for new anti-mycobacterial drugs with novel targets. We previously evaluated series of 2-aminothiazoles activity against tuberculosis. In this study, we identify the glycolytic enzyme enolase as target these molecules using pull down studies. demonstrate that modulation level expression affects sensitivity 2-aminothiazoles; increased leads resistance...
A family of compounds typified by an anthranilic amide 1 was identified from a whole-cell screening effort targeted at identifying that disrupt pH homeostasis in Mycobacterium tuberculosis. demonstrated bactericidal activity against non-replicating M. tuberculosis 4.5 buffer (MBC4.5 = 6.3 μM). Exploration the structure-activity relations failed to simplify scaffold. The antitubercular proved dependent on lipophilicity and planarity molecule directly correlated with mammalian cytotoxicity....