A5055334453- Tuberculosis Research and Epidemiology
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Cancer Treatment and Pharmacology
- Cancer therapeutics and mechanisms
- Microtubule and mitosis dynamics
- Biochemical and Molecular Research
- Mycobacterium research and diagnosis
- Antibiotic Resistance in Bacteria
- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Synthetic Organic Chemistry Methods
- Parasites and Host Interactions
- Computational Drug Discovery Methods
- Microbial Natural Products and Biosynthesis
- Biological Activity of Diterpenoids and Biflavonoids
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- Plant biochemistry and biosynthesis
- Pneumocystis jirovecii pneumonia detection and treatment
- Quinazolinone synthesis and applications
- Malaria Research and Control
- 14-3-3 protein interactions
- Mitochondrial Function and Pathology
- Metal complexes synthesis and properties
Novartis (United States)
2017-2025
Novartis (Ireland)
2020-2025
Novartis (Switzerland)
2025
Health Biomed (China)
2025
Novartis (Singapore)
2008-2023
Swiss Tropical and Public Health Institute
2020
University of Basel
2020
University of Bern
2020
Johns Hopkins University
2020
Genomics Institute of the Novartis Research Foundation
2019
The persistence of Mycobacterium tuberculosis despite prolonged chemotherapy represents a major obstacle for the control tuberculosis. mechanisms used by Mtb to persist in quiescent state are largely unknown. Chemical genetic and approaches were here study physiology hypoxic nonreplicating mycobacteria. We found that intracellular concentration ATP is five six times lower cells compared with aerobic replicating bacteria, making them exquisitely sensitive any further depletion. show de novo...
Candidate antibacterials are usually identified on the basis of their in vitro activity. However, apparent inhibitory activity new leads can be misleading because most culture media do not reproduce an environment relevant to infection vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism affect antimicrobial Novel pyrimidine-imidazoles (PIs) were a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated potent...
Taxol possesses an unusual chemical structure, a unique mechanism of action, and demonstrated activity in human malignancies. It is the only antitumor agent that has binding site on microtubule polymer. The interaction with polymer results formation stable bundles cellular microtubules are resistant to depolymerization. Although it become evident microtubule, specifically beta-tubulin, target for Taxol, no information available drug. In this report, we demonstrate 3'-(p-azidobenzamido)taxol,...
Photoaffinity labeling methods are being used to define the molecular contacts between taxol and its target protein, tubulin. Our laboratory has demonstrated previously that [3H]3'-(p-azidobenzamido)taxol photolabels N-terminal 31 amino acids of beta-tubulin (Rao, S., Krauss, N.E., Heerding, J.M., Swindell, C.S., Ringel, I., Orr, G.A., Horwitz, S.B. (1994) J. Biol. Chem. 269, 3132-3134). The interaction a second photoaffinity analogue taxol, [3H]2-(m-azidobenzoyl)taxol, with tubulin been...
Target practice: The target of the antibiotic cyclomarin A was identified in Mycobacterium. Cyclomarin (see structure) binds regulatory subunit Clp protease complex with high affinity resulting elevated proteolysis and cell death. property to kill both growing nonreplicating mycobacteria makes a promising for antitubercular drug discovery. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They...
Abstract Objectives The discovery and development of TB drugs has met limited success, with two new approved over the last 40 years. Part difficulty resides in lack well-established vitro or vivo targets potency physicochemical pharmacokinetic parameters. In an attempt to benchmark compare such properties for anti-TB agents, we have experimentally determined compiled these parameters 36 compounds, using standardized centralized assays, thus ensuring direct comparability across drug classes....
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic lipid profiling studies likely molecular target MmpL3, transporter trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 NITD-349, showed potent activity both...
Growing evidence suggests that the presence of a subpopulation hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for prolonged duration tuberculosis treatment. The discovery new antitubercular agents active against this may help in developing strategies to shorten time therapy. Recently, maintenance low level bacterial respiration was shown be point metabolic vulnerability Mycobacterium tuberculosis. Here, we describe development model identify compounds...
4-Hydroxy-2-pyridones, direct inhibitors of the mycobacterial protein InhA, are active against multidrug-resistant Mycobacterium tuberculosis .
Mycobacterium tuberculosis (Mtb) is an aerobic bacterium that persists intracellularly in host macrophages and has evolved diverse mechanisms to combat survive oxidative stress. Here we show a novel F(420) -dependent anti-oxidant mechanism protects Mtb against Inactivation of the fbiC gene results cofactor -deficient mutant hypersensitive stress exhibits reduction NADH/NAD(+) ratios upon treatment with menadione. In agreement recent hypothesis on being important component pathway resulting...
Cyclomarin A (CymA) was identified as a mycobactericidal compound targeting ClpC1. However, the target based on pulldown experiments and in vitro binding data, without direct functional evidence mycobacteria. Here we show that CymA specifically binds to N-terminal domain of In addition have determined co-crystal structure bound ClpC1 high resolution. Based complex several mutations were engineered into ClpC1, which showed reduced vitro. The mutants overexpressed mycobacteria two resistance...
Kinetoplastid parasites have caused human disease for millennia. Significant achievements been made toward developing new treatments leishmaniasis (particularly on the Indian subcontinent) and African trypanosomiasis (HAT). Moreover, sustained decrease in incidence of HAT has prospect elimination a tantalizing reality. Despite gains, no chemical or biological entities to treat kinetoplastid diseases registered more than three decades, work is needed discover safe effective therapies patients...
Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor kinetoplastid proteasome, which cleared parasites in murine models leishmaniasis, Chagas disease, human African trypanosomiasis. Here, describe characterization LXE408, structurally related kinetoplastid-selective proteasome currently Phase 1...
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease human African trypanosomiasis (HAT). Improved HAT treatments available, but therapies rely on two nitroheterocycles, suffer from lengthy drug regimens safety concerns that frequent treatment discontinuation. We performed phenotypic screening against trypanosomes identified a class cyanotriazoles (CTs) with potent trypanocidal activity both vitro mouse models HAT....
Identification of novel drug targets is a key component modern discovery. While antimalarial are often identified through the mechanism action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space also constrained by existing compound libraries phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed Plasmodium falciparum genome 867 candidate with evidence...
Photoaffinity labeling methods have allowed a definition of the sites interaction between Taxol and its cellular target, microtubule, specifically β-tubulin. Our previous studies indicated that [<sup>3</sup>H]3′-(<i>p</i>-azidobenzamido)Taxol photolabels N-terminal 31 amino acids β-tubulin (Rao, S., Krauss, N. E., Heerding, J. M., Swindell, C. Ringel, I., Orr, G. A., Horwitz, S. B. (1994) <i>J. Biol. Chem.</i> 269, 3132–3134) [<sup>3</sup>H]2-(<i>m</i>-azidobenzoyl)Taxol peptide containing...
Journal Article Direct Photoaffinity Labeling of Tubulin With Taxol Get access Srinivasa Rao, Rao Department Molecular Pharmacology and cell Biology, Albert Einstein College MedicineBronx, N.Y Search for other works by this author on: Oxford Academic PubMed Google Scholar Susan Band Horwitz, Horwitz * Correspondence to: B. Ph.D., Pharmacology, Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Israel Ringel The Hebrew University-Hadassah Medical SchoolJerusalem, JNCI: the National Cancer...
Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One the hits, indole-2-carboxamide analog (1), had low micromolar potency Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and aqueous solubility. Structure–activity relationship studies revealed that attaching alkyl groups to cyclohexyl ring significantly improved Mtb activity but reduced Furthermore, chloro, fluoro, or cyano...
High-throughput screening of a library small polar molecules against Mycobacterium tuberculosis led to the identification phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing moiety with methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents designed and executed explore structure-activity relationships respect N-benzyl substituent, leading compounds nanomolar activity. The frontrunner (5h) from these studies well...
Mycobacteria store triacylglycerols (TGs) in the form of intracellular lipid droplets (LDs) during hypoxia-induced nonreplicating persistence. These bacteria are phenotypically drug-resistant and therefore believed to be cause for prolonged tuberculosis treatment. LDs also associated with bacilli patient sputum hypervirulent strains. Although proteins bound well characterized eukaryotes, identities functions such have not been described mycobacteria. Here, we identified five proteins: Tgs1...