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Identification and heterologous expression of the globomycin biosynthetic gene cluster

Synthetic and Systems Biotechnology 2023年第2期8卷 206-212页

作者： Daniel Oves-Costales Tetiana Gren Eva Baggesgaard Sterndorff Jesús Martín Francisco Javier Ortiz-Lopez Tue S.Jørgensen Xinglin Jiang Fernando Roman-Hurtado Fernando Reyes olga genilloud Tilmann Weber Fundacion MEDINA Centro de Excelencia en Investigaci´on de Medicamentos Innovadores en AndalucíaAvda del Conocimiento 3418016ArmillaGranadaSpain The Novo Nordisk Foundation Center for Biosustainability Technical University of DenmarkKemitorvetbuilding 2202800 Kgs.LyngbyDenmark

Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative *** mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II(LspA),which is absent in eukaryotes and considered an attractive target for the development of new *** its interesting biological properties,the gene cluster encoding its biosynthesis has not yet been *** this study we employed a genome-mining approach in the globomycin-producing Streptomyces ***-278952 to identify a candidate gene cluster responsible for its biosynthesis.A null mutant was constructed using CRISPR base editing where production was abolished,strongly suggesting its involvement in the *** putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146,therefore unambigu-ously linking globomycin and its biosynthetic gene *** work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties.

关键词： Globomycin Signal peptidase II Cyclic lipodepsipeptide Genome mining CRISPR-cBEST Heterologous expression

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Discovery of gargantulides B and C,new 52-membered macrolactones from Amycolatopsis *** absolute stereochemistry of the gargantulide family

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Organic Chemistry Frontiers 2022年第2期9卷 462-470页

作者： Daniel Carretero-Molina Francisco Javier Ortiz-López Tetiana Gren Daniel Oves-Costales Jesús Martín Fernando Román-Hurtado Tue Sparholt Jorgensen Mercedes de la Cruz Caridad Díaz Francisca Vicente Kai Blin Fernando Reyes Tilmann Weber olga genilloud Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en AndalucíaAvda.del Conocimiento 3418016 ArmillaGranadaSpain The Novo Nordisk Foundation Center for Biosustainability Technical University of DenmarkKemitorvetbuilding 2202800 Kgs.LyngbyDenmark

Gargantulides B and C,two new and highly complex 52-membered glycosylated macrolactones,were isolated from Amycolatopsis *** CA-230715 during an antibacterial screening *** structures of these giant macrolides were elucidated by 2D NMR spectroscopy and shown to be related to gargantulide A,although containing additional β-glucopyranose and/orα-arabinofuranose monosaccharides separately attached to their *** sequencing allowed the identification of a strikingly large 216 kbp biosynthetic gene cluster,among the largest type Ⅰ PKS clusters described so far,and the proposal of a previously unreported biosynthetic pathway for gargantulides *** absolute configurations of gargantulides B and C were assigned based on a combination of NMR and bioinformatics analysis of ketoreductase and enoylreductase domains within the multimodular type Ⅰ *** addition,the absolute stereochemistry of gargantulide A has now been revised and *** B and C display potent antibacterial activity against a set of drug-resistant Gram-positive bacteria and moderate activity against the clinically relevant Gram-negative pathogen Acinetobacter baumannii.

关键词： absolute membered backbone

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HCS strategy targeting dysregulation of the VHL/HIF pathway for drug discovery

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Advances in Bioscience and Biotechnology 2013年第3期4卷 398-405页

作者： Bastien Cautain Nuria de Pedro Maria Munoz de Escalona Jose R.Tormo olga genilloud Francisca Vicente Screening and Target Validation Department Fundacion MedinaGranadaSpain

One-third of top-selling drugs are derived from natural products. When only a fraction of the bioactive natural products diversity has been explored, huge opportunities still remain for discovering novel leads for the development of new drugs. Clear cell renal cell carcinoma (ccRCC) is a highly vascular tumour arising from epithelial elements. Mutations in the Von Hippel-Lindau (VHL) gene are responsible for VHL disease and arise in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer. Renal carcinoma cell lines with naturally occurring VHL mutations (RCC4 VA) and their genetically matched wild-type VHL (RCC4 VHL) counterparts were seeded onto 96-well plates and allowed to attach overnight. Fungal extracts were tested on both cell lines. Clinically useful antitumor agents were used as positive controls and as reference points to establish the efficacy and selectivity of the new compounds. Renal cell carcinoma cell lines expressing VHL or not were treated with Carboxyfluorescein succinimidyl ester (CFSE). The day after cell inoculation, extracts were added and during the following days of incubation, fluorescence intensity was measured as a surrogate marker for cell viability. The most promising extracts selectively inhibited growth of pVHL-defi- cient cells but not of wild-type VHL cells. We used High Content Bio-imaging, a complete cellular imaging workflow that integrates instruments and software to acquire and analyze images, to evaluate their effect. Cell imaging can reveal effects that would be overlooked by other cell assay approaches. This target-based whole cell screen is a new strategy, which ensures cell permeability and target selectivity especially in natural product screening where natural product purification is a labour of extensive work. This approach permitted a dynamic study where fluorescence was measured without affecting cell viability and enabling a better detection of cytotoxic effects such as autophagy, senescence or

关键词： High Content Screening Natural Products HIF Drug Discovery

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Evaluation of the effect of compound aqueous solubility in cytochrome P450 inhibition assays

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Advances in Bioscience and Biotechnology 2013年第5期4卷 628-639页

作者： José Pérez Caridad Díaz Irene G. Salado Daniel I. Pérez Fernando Peláez olga genilloud Francisca Vicente Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid Spain Fundación Centro de Excelencia Investigación de Medicamentos Innovadores de Andalucía Granada Spain Instituto de Química Médica Madrid Spain

It is a common practice in drug discovery organizations to screen new chemical entities in order to predict future drug-drug interactions. For this purpose, there are two main assay strategies, one based on recombinant cytochrome P450 (rCYP) enzymes and fluorescent detection, and other on human liver microsomes (HLM) and liquid chromatography coupled to mass spectrometry. Many authors have reported a poor correlation between both technologies, giving rise to concerns about the usefulness of fluorometric methods for predicting drug-drug interactions. In this study, we investigated the role that compound aqueous kinetic solubility may play in this lack of correlation. We found that drug discovery compounds with unacceptable kinetic solubility, measured by a turbidimetric solutibility assay, tended to yield higher IC50 values in in vitro models based on human liver microsomes, whereas compounds with kinetic solubility values higher than 50 μM showed very similar IC50 values in both in vitro models. Our results show that the turbidimetric solubility assay is a useful tool to identify those discovery compounds that may require further investigation in order to avoid overlooking future drug-drug interactions.

关键词： CYP Inhibition Fluorogenic Substrates Drug Safety Human Liver Microsomes Drug-Drug Interactions

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