A5011015453- Tuberculosis Research and Epidemiology
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Trypanosoma species research and implications
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthesis and biological activity
- Antibiotic Resistance in Bacteria
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- Synthesis of β-Lactam Compounds
- Synthesis and Catalytic Reactions
- Synthesis and Biological Evaluation
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- Epilepsy research and treatment
- Diet, Metabolism, and Disease
- Synthesis and Biological Activity
- Click Chemistry and Applications
- Chemical Reactions and Isotopes
- Computational Drug Discovery Methods
- Mycobacterium research and diagnosis
- Advancements in Transdermal Drug Delivery
- Microbial Metabolic Engineering and Bioproduction
- Phytochemistry and Bioactivity Studies
- Plant nutrient uptake and metabolism
UCB Pharma (Belgium)
2016-2023
University of Minnesota
2008-2019
École Polytechnique Fédérale de Lausanne
2010-2018
University of Manchester
2005-2013
Comenius University Bratislava
2013
National Institute of Allergy and Infectious Diseases
2008
American Type Culture Collection
2008
Engineering and Physical Sciences Research Council
2005
University of Southampton
2005
University of Lisbon
2001-2005
The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. targets the DprE1 catalytic component of essential enzyme decaprenylphosphoryl-β-D-ribofuranose-2'-epimerase, thus blocking biosynthesis arabinans, vital components mycobacterial cell walls. Crystal structures DprE1, in its native form and complex BTZ043, reveal formation semimercaptal adduct between an active-site cysteine, as well contacts to neighboring lysine residue. Kinetic studies confirm...
The flavo-enzyme DprE1 catalyzes a key epimerization step in the decaprenyl-phosphoryl d-arabinose (DPA) pathway, which is essential for mycobacterial cell wall biogenesis and targeted by several new tuberculosis drug candidates. Here, using differential radiolabeling with DPA precursors high-resolution fluorescence microscopy, we disclose unexpected extracytoplasmic localization of periplasmic synthesis DPA. Collectively, this explains vulnerability remarkable potency best inhibitors.
Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC 3.1 μM, is bactericidal active intracellular bacteria. To investigate its mechanism action, we isolated mutants resistant sequenced their genomes. Mutations were found in rv3405c, coding for transcriptional repressor divergently expressed rv3406 gene....
5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis mycobactins. Herein, we report structure-based design, synthesis, biochemical, and biological evaluation comprehensive systematic series analogues, exploring structure−activity relationship purine nucleobase domain Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent...
4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by genome sequencing mutants raised against AQs, decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) primary target responsible for antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors DprE1...
8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of BTZ scaffold to be crucial for mechanism action, which involves formation a semimercaptal bond with Cys387 active site DprE1. To date, substitution has led extensive loss antimycobacterial activity. Here, we report...
The synthesis, biochemical, and biological evaluation of a systematic series 2-triazole derivatives 5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) are described as inhibitors aryl acid adenylating enzymes (AAAE) involved in siderophore biosynthesis by Mycobacterium tuberculosis. Structure−activity relationships revealed remarkable ability to tolerate wide range substituents at the 4-position triazole moiety, majority compounds possessed subnanomolar apparent inhibition constants. However,...
Tuberculosis is still a leading cause of death in developing countries, for which there an urgent need new pharmacological agents. The synthesis the novel antimycobacterial drug class benzothiazinones (BTZs) and identification their cellular target as DprE1 (Rv3790), component decaprenylphosphoryl-β-d-ribose 2′-epimerase complex, have been reported recently. Here, we describe characterization resistance mechanism to BTZ Mycobacterium smegmatis. overexpression nitroreductase NfnB leads...
Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency BTZs is explained by their specificity for target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular covalent binding the activated form compound critical cysteine 387 residue enzyme. To probe role C387, we used promiscuous site-directed mutagenesis introduce other codons at this position into dprE1 M....
The human pathogen Acinetobacter baumannii produces a siderophore called acinetobactin that is derived from one molecule each of threonine, histidine, and 2,3-dihydroxybenzoic acid (DHB). activity several nonribosomal peptide synthetase (NRPS) enzymes used to combine the building blocks into final molecule. synthesis pathway initiates with self-standing adenylation enzyme, BasE, activates DHB covalently transfers it pantetheine cofactor an aryl-carrier protein BasF, strategy shared many...
Abstract A simple steady‐state kinetic high‐throughput assay was developed for the salicylate synthase MbtI from Mycobacterium tuberculosis , which catalyzes first committed step of mycobactin biosynthesis. The mycobactins are small‐molecule iron chelators produced by M. and their biosynthesis has been identified as a promising target development new antitubercular agents. miniaturized to 384‐well plate format screening performed at National Screening Laboratory Regional Centers Excellence...
Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli. We performed high-throughput screening against BasE, which involved siderophore A. identified...
The design and synthesis of a fluorescent probe Fl-Sal-AMS 6 based on the tight-binding inhibitor 5'- O-[ N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is described for aryl acid adenylating enzymes (AAAEs) known as MbtA, YbtE, EntE, VibE, DhbE, BasE involved in siderophore biosynthesis from Mycobacterium tuberculosis, Yersinia pestis, Escherichia coli, Vibrio cholerae, Bacillus subtilis, Acinetobacter baumannii, respectively. was successfully used to develop fluorescence polarization assay these...
Two transcriptional regulators in the bacterium Ralstonia solanacearum (VsrAD and PhcA) that play a central role for virulence were shown to affect secondary metabolism as well; this led identification of new natural product, ralfuranone. The results shed light on regulation biosynthetic capacities plant pathogen.
The dual-specificity protein kinase monopolar spindle 1 (Mps1) is a central component of the mitotic assembly checkpoint (SAC), sensing mechanism that prevents anaphase until all chromosomes are bioriented on metaphase plate. Partial depletion Mps1 levels sensitizes transformed, but not untransformed, human cells to therapeutic doses anticancer agent Taxol, making it an attractive novel cancer target. We have previously determined X-ray structure catalytic domain in complex with...
Abstract Nitroarenes are less preferred in drug discovery due to their potential be mutagenic. However, several nitroarenes were shown promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group these compounds is activated through different mechanisms, both enzymatic non‐enzymatic, mycobacteria prior binding the target interest. From a whole‐cell screening program, we identified novel lead nitrobenzothiazole (BT) series that...