Publications by Ruben Hartkoorn

Synthesis and Structure-Activity Relationship Studies of C2-Modified Analogs of the Antimycobacterial Natural Product Pyridomycin

Stewart Cole, Ruben Hartkoorn, Anthony Vocat

A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond foun ...

AMER CHEMICAL SOC2020

Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs

Stewart Cole, Ruben Hartkoorn

2018

Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria

Kai Johnsson, Gaëlle Séraphine Kolly, Graham Knott, John McKinney, Stewart Cole, Neeraj Dhar, Monica Rengifo Gonzalez, Ruben Hartkoorn, Isabella Santi, Edina Rita Székely, François Signorino-Gelo, Jan Lars Rybniker, Anthony Vocat

There is an urgent need to discover new antitubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that ...

Wiley-Blackwell2017

The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis

John McKinney, Stewart Cole, Neeraj Dhar, Claudia Sala, Ruben Hartkoorn, Raphael Christopher Sommer, Anthony Vocat, Andréanne Lupien

VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine mo ...

Amer Chemical Soc2017

Discovery and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity against Mycobacterium tuberculosis

Stewart Cole, Ruben Hartkoorn, Anthony Vocat

An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin i ...

Amer Chemical Soc2017

Micrococcin P1-A bactericidal thiopeptide active against Mycobacterium tuberculosis

Stewart Cole, Ruben Hartkoorn, Andrej Benjak

The lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance reinforces the need for the discovery of novel antibiotics. This is particularly true for tuberculosis (TB) for which 3.7% of new cases and 20% of pre ...

Elsevier2016

Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis

Stewart Cole, Neeraj Dhar, Claudia Sala, Ruben Hartkoorn, Ming Zhang, Benoit Lechartier, Anthony Vocat

Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potenc ...

American Society for Microbiology2015

2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1

Gaëlle Séraphine Kolly, Stewart Cole, Neeraj Dhar, Florence Pojer, Ruben Hartkoorn, Joao Pedro De Almeida Neres

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 mu M, ...

American Chemical Society2015

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

Stewart Cole, Ruben Hartkoorn

To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosi ...

Elsevier2015

Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Stewart Cole, Ruben Hartkoorn, Edina Rita Székely

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based ap ...

Elsevier2015

Whole cell screen based identification of spiropiperidines with potent antitubercular properties

Stewart Cole, Ruben Hartkoorn

Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent ...

Elsevier2015

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

Gaëlle Séraphine Kolly, Stewart Cole, Ruben Hartkoorn, Joao Pedro De Almeida Neres, Anthony Vocat, Trent Michael Conroy, Jérémie Piton

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-beta-D-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studie ...

American Society for Microbiology2015

4-Pyrimidinylamino-benzenesulfonamide derivatives and their use for the inhibition of polo-like kinase 1 (PLK1) for the treatment of cancer and their use for the treatment of bacterial infections

Stewart Cole, Ruben Hartkoorn, Edina Rita Székely

The present invention relates to 4-pyrimidinylamino-benzenesulfonamide derivatives of general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, regioisomeric and polymorphic forms thereof, processes for manufacturing of them, the use o ...

2015

Cross-Resistance between Clofazimine and Bedaquiline through Upregulation of MmpL5 in Mycobacterium tuberculosis

Stewart Cole, Swapna Uplekar, Ruben Hartkoorn

The antileprosy drug clofazimine is also of interest for the treatment of multidrug-resistant tuberculosis. To understand possible resistance mechanisms, clofazimine-resistant Mycobacterium tuberculosis mutants were isolated in vitro, and, unexpectedly, fo ...

Amer Soc Microbiology2014

Pyridomycin bridges the NADH- and substratebinding pockets of the enoyl reductase InhA

Stewart Cole, Florence Pojer, Ruben Hartkoorn, Joao Pedro De Almeida Neres

Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-bi ...

Nature Publishing Group2014

Rv2466c Mediates the Activation of TP053 To Kill Replicating and Non-replicating Mycobacterium tuberculosis

Stewart Cole, Ruben Hartkoorn, Anthony Vocat

The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) compoun ...

American Chemical Society2014

Assessing the essentiality of the decaprenyl-phospho-D-arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants

Gaëlle Séraphine Kolly, John McKinney, Stewart Cole, Neeraj Dhar, Claudia Sala, Ruben Hartkoorn

In Mycobacterium tuberculosis the decaprenyl-phospho-d-arabinofuranose (DPA) pathway is a validated target for the drugs ethambutol and benzothiazinones. To identify other potential drug targets in the pathway, we generated conditional knock-down mutants o ...

Wiley-Blackwell2014

Mechanism of Action of 5-Nitrothiophenes against Mycobacterium tuberculosis

Stewart Cole, Ruben Hartkoorn

On using the streptomycin-starved 18b strain as a model for nonreplicating Mycobacterium tuberculosis, we identified a 5-nitrothiophene compound as highly active but not cytotoxic. Mutants resistant to 5-nitrothiophenes were found be cross-resistant to the ...

Amer Soc Microbiology2014

Towards a new combination therapy for tuberculosis with next generation benzothiazinones

Paul Joseph Dyson, Thierry Buclin, Stewart Cole, Florence Pojer, Ruben Hartkoorn, Ming Zhang, Benoit Lechartier, Joao Pedro De Almeida Neres, Anthony Vocat

The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) a ...

2014

Anticytolytic Screen Identifies Inhibitors of Mycobacterial Virulence Protein Secretion

Stewart Cole, Claudia Sala, Jeffrey Chen, Ruben Hartkoorn, Ming Zhang, Edina Rita Székely, Jan Lars Rybniker, Anthony Vocat, Andrej Benjak

Mycobacterium tuberculosis (Mtb) requires protein secretion systems like ESX-1 for intracellular survival and virulence. The major virulence determinant and ESX-1 substrate, EsxA, arrests phagosome maturation and lyses cell membranes, resulting in tissue d ...

Cell Press2014