Publications de Joao Pedro De Almeida Neres

Fluorescent Benzothiazinone Analogues Efficiently and Selectively Label Dpre1 in Mycobacteria and Actinobacteria

Paul Joseph Dyson, Thierry Laroche, John McKinney, Stewart Cole, Neeraj Dhar, Raphael Christopher Sommer, Joao Pedro De Almeida Neres, Raju Mukherjee, Jérémie Piton

Benzothiazinones (BTZ) are highly potent bactericidal inhibitors of mycobacteria and the lead compound, BTZ043, and the optimized drug candidate, PBTZ169, have potential for the treatment of tuberculosis. Here, we exploited the tractability of the BTZ scaf ...

2018

Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity

Joao Pedro De Almeida Neres

Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro gr ...

Wiley-V C H Verlag Gmbh2016

Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis

Gaëlle Séraphine Kolly, Stewart Cole, Claudia Sala, Benoit Lechartier, Joao Pedro De Almeida Neres, Stefanie Boy-Röttger, Jan Lars Rybniker, Shi-Yan Caroline Foo, Jérémie Piton, Andréanne Lupien

Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-D ...

American Society for Microbiology2016

DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization

Gaëlle Séraphine Kolly, Stewart Cole, Joao Pedro De Almeida Neres, Raju Mukherjee

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 r ...

American Chemical Society2015

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

Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose 2 '-oxidase

Stewart Cole, Florence Pojer, Anirban Ghosh, Joao Pedro De Almeida Neres

We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of deca ...

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-Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity

John McKinney, Neeraj Dhar, Joao Pedro De Almeida Neres, François Signorino-Gelo

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequenci ...

Amer Chemical Soc2014

Selective detection of epimeric pentose saccharides at physiological pH using a fluorescent receptor

Matthew Gibson, Elizabeth Fullam, Joao Pedro De Almeida Neres

Epimerisation between ribofuranose and arabinofuranose sugars is crucial in several biosynthetic pathways, but is typically challenging to monitor. Here, we have screened for fluorescent boronic acids that can be used as molecular probes for the specific d ...

Elsevier Sci Ltd2014

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

DprE1-from the Discovery to the Promising Tuberculosis Drug Target

Joao Pedro De Almeida Neres

Several groups working in the field of the development of new antituberculosis drugs have recently reported active compounds targeting mycobacterial enzyme DprE1. Along with its counterpart, DprE2, it catalyses a unique epimerization reaction resulting in ...

Bentham Science Publ Ltd2014

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

Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis

Paul Joseph Dyson, John McKinney, Stewart Cole, Neeraj Dhar, Florence Pojer, Elizabeth Fullam, Joao Pedro De Almeida Neres

The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. BTZ043 targets the DprE1 catalytic component of the essential enzyme decaprenylphosphoryl-beta-D-ribofuranose-2'-epimerase, thus blocking biosynthesis of arabin ...

American Association for the Advancement of Science2012

Towards a new tuberculosis drug: pyridomycin - nature's isoniazid

Stewart Cole, Claudia Sala, Florence Pojer, Sophie Magnet, Swapna Uplekar, Ruben Hartkoorn, Joao Pedro De Almeida Neres, Raju Mukherjee

Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an importan ...

Wiley Open Access2012

Biological and structural characterization of the Mycobacterium smegmatis nitroreductase NfnB, and its role in benzothiazinone resistance

Stewart Cole, Giulia Manina, Joao Pedro De Almeida Neres

Summary Tuberculosis is still a leading cause of death in developing countries, for which there is an urgent need for new pharmacological agents. The synthesis of the novel antimycobacterial drug class of benzothiazinones (BTZs) and the identification of t ...

2010