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Tres Cantos, Spain

Rebollo-Lopez M.J.,Glaxosmithkline | Lelievre J.,Glaxosmithkline | Alvarez-Gomez D.,Glaxosmithkline | Castro-Pichel J.,Glaxosmithkline | And 23 more authors.
PLoS ONE | Year: 2015

As a follow up to the antimycobacterial screening exercise and the release of GSKs first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike. © 2015 Rebollo-Lopez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Kumar A.,Seattle Biomedical Research Institute | Guardia A.,Glaxosmithkline | Colmenarejo G.,Research Center Basica | Perez E.,Glaxosmithkline | And 11 more authors.
ACS Infectious Diseases | Year: 2015

Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy studies of tuberculosis, we paired knowledge and tools developed in academia with the infrastructure and chemistry resources of a large pharmaceutical company. Together we curated a focused library of 2508 potential antifolates, which were then tested for activity against live Mtb. We identified 210 primary hits, confirmed the on-target activity of potent compounds, and now report the identification and characterization of 5 hit compounds, representative of 5 different chemical scaffolds. These antifolates have potent activity against Mtb and represent good starting points for improvement that could lead to in vivo efficacy studies. © 2015 American Chemical Society.

Xu D.,Merck Frosst Center for Therapeutic Research | Ondeyka J.,Merck And Co. | Harris G.H.,Merck And Co. | Zink D.,Merck And Co. | And 9 more authors.
Journal of Natural Products | Year: 2011

In a whole-cell mechanism of action (MOA)-based screening strategy for discovery of antifungal agents, Candida albicans was used, followed by testing of active extracts in the C. albicans fitness test (CaFT), which provides insight into the mechanism of action. A fermentation extract of an undescribed species of Metulocladosporiella that inhibited proteasome activity in a C. albicans fitness test was identified. The chemical genomic profile of the extract contained hypersensitivity of heterozygous deletion strains (strains that had one of the genes of the diploid genes knocked down) of genes represented by multiple subunits of the 25S proteasome. Two structurally related peptide aldehydes, named fellutamides C and D, were isolated from the extract. Fellutamides were active against C. albicans and Aspergillus fumigatus with MICs ranging from 4 to 16 μg/mL and against fungal proteasome (IC 50 0.2 μg/mL). Both compounds showed proteasome activity against human tumor cell lines, potently inhibiting the growth of PC-3 prostate carcinoma cells, but not A549 lung carcinoma cells. In PC-3 cells compound treatment produced a G2M cell cycle block and induced apoptosis. Preliminary SAR studies indicated that the aldehyde group is critical for the antifungal activity and that the two hydroxy groups are quantitatively important for potency. © 2011 The American Chemical Society and American Society of Pharmacognosy.

Pelaez F.,Spanish National Cancer Research Center | Collado J.,Oficina Espanola de Patentes y Marcas | Overy D.P.,University of Prince Edward Island | Gonzlez del Val A.,Research Center Basica | And 7 more authors.
Mycology | Year: 2011

Glarea lozoyensis is an anamorphic ascomycete that produces pneumocandin B0, the starting molecule for the synthesis of the antifungal drug caspofungin (CANCIDASTM). Glarea lozoyensis was first isolated in 1985 from a water sample from Madrid, Spain. Until now, only the original strain was known, but we have discovered new strains from Argentina and the USA. Molecular phylogenetic reference to a 28S rDNA database of antibiotic-producing fungi quickly identified these strains as being conspecific with G. lozoyensis. Bayesian inference phylogeny of ITS, 28S rDNA and α-actin gene fragments revealed that G. lozoyensis is related to species of the genus Cyathicula (Helotiales). Glarea lozoyensis was not conspecific with any of the Cyathicula species sequenced, although it appears to share a common ancestor. Glarea lozoyensis and Cyathicula strains were fermented on nutritional microarrays in 96-well plates. Cyathicula extracts did not show antifungal activity and did not produce pneumocandins, whereas potent antifungal activity and pneumocandin A0 production were confirmed for the four G. lozoyensis isolates. Also, culture morphology differed, with G. lozoyensis strains producing a dark brown, profusely sporulating mycelium with pigmented multicellular conidia accumulating in conidial masses, while all Cyathicula species tested in culture formed hyaline to light brown mycelia and lacked conidia. The chemistry and taxonomic distribution of the echinocandin class of antifungals is comprehensively reviewed. © 2011 Mycological Society of China.

Herath K.,Merck And Co. | Jayasuriya H.,Merck And Co. | Zink D.L.,Merck And Co. | Sigmund J.,Merck And Co. | And 11 more authors.
Journal of Natural Products | Year: 2012

Drug-resistant bacteria continue to make many existing antibiotic classes ineffective. In order to avoid a future epidemic from drug-resistant bacterial infections, new antibiotics with new modes of action are needed. In an antibiotic screening program for new drug leads with new modes of action using antisense Staphylococcus aureus Fitness Test screening, we discovered a new tetramic acid, methiosetin, from a tropical sooty mold, Capnodium sp. The fungus also produced epicorazine A, a known antibiotic. The structure and relative configuration of methiosetin was elucidated by 2D NMR and ESIMS techniques. Methiosetin and epicorazine A showed weak to modest antibacterial activity against S. aureus and Haemophilus influenzae. The isolation, structure elucidation, and antibacterial activity of both compounds are described. © 2012 The American Chemical Society and American Society of Pharmacognosy.

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