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Design and biological activity of phosphomannose isomerase (PMI) inhibitors from Xanthomonas sp for treatment and prevention of citrus canker

Abstract

Citrus canker, mainly caused by the bacterium Xanthomonas citri subsp. citri (XAC), is one of the most important citrus diseases, with a significant impact on the Brazilian economy. Studies of comparative proteomic analysis of the surface of infecting and non-infecting cells of XAC carried out with the collaborating group at the Laboratory of Biochemistry and Applied Molecular Biology (LBBMA) of the Department of Genetics (DGE) of the Federal University of São Carlos - UFSCar, pointed to a promising enzyme that could be used as a biological target for designing inhibitors to control the disease: phosphomannose isomerase (PMI), which catalyzes the interconversion of fructose-6-phosphate (F6P) and mannose-6-phosphate ( M6P), in addition to allowing the synthesis of GDP-mannose in eukaryotic organisms. PMI is considered a potential therapeutic target due to its participation in the survival and pathogenicity of several microorganisms, such as S. cerevisiae, C. albicans, M. smegmatis, L. mexicana and Xanthomonas sp. The enzyme has been shown to be a very promising target for the development of new antifungal treatments, since the lack of PMI activity in yeast cells can lead to cell lysis, which may be due to its role in the formation of cell walls and in the biosynthesis of capsular polysaccharides. Furthermore, M6P is an important signaling molecule, especially for transport to lysosomes: disorders that interfere with the activity of this enzyme can affect the cellular ability to rapidly produce M6P from abundant F6P and therefore vesicle trafficking to lysosomes and endosomes can be altered, negatively impacting the cell.This theoretical-experimental research project aims to continue the recently started computational design and development with PMI inhibitors, which has already resulted in a first patent (SILVA, C. H. T. P. et al., Registration number: BR10202100866, title: " USE OF CHEMICAL COMPOUNDS INHIBITORS OF PHOSPHOMANOSE ISOMERASE TO CONTROL CITRUS CANCER AND PHYTOPATHOLOGIES ASSOCIATED WITH THE GENUS XANTHOMONAS", Institution of registration: INPI - National Institute of Industrial Property. Filing: 05/04/2021), now with a view to new plans, in based on the optimization of the lead and most potent compounds already obtained (with an IC50 inhibitory concentration obtained of up to 10 nM), which includes the development, by in silico optimization and obtaining/synthesis of new and more potent chemical compounds capable of inhibiting the enzyme PMI of XAC, as well as investigation of its contributions to the reduction of virulence of the bacterium and to the control of the infection in the plant. As few PMI inhibitors have been reported for the bacteria of interest and even for other species, and always with low affinity/potency described, it becomes appropriate to plan new potential inhibitors of this enzyme and evaluate their biological activities, together with our collaborating groups. Finally, the compounds already screened as well as the new ones will have their ADME/Tox and pharmacodynamic properties optimized by 'Lead Optimization' and QSAR (Quantitative Structure-Activity Relationships) methodologies, and new compounds thus planned and modified should be obtained commercially and/ or by synthesis (together with our collaborating group at the Facultad de Farmácia of the Universidad de Granada, Spain), and tested in vitro and in vivo, with a view to developing a useful and effective bactericidal solution in the prevention of citrus canker, with low or no toxicity to the environment and consumption of the fruit, easy to obtain/produce, as an alternative to the only methodology currently used, with copper and more toxic and, therefore, with broad interest from producers as well as consumers of citrus products. (AU)

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