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Discovery of ligands as Xanthomonas albilineans Dihydropteroate synthase inhibitors

Grant number: 17/17816-4
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): January 23, 2018
Effective date (End): January 22, 2019
Field of knowledge:Biological Sciences - Biophysics
Principal Investigator:Rafael Victorio Carvalho Guido
Grantee:Andrew Albert de Oliveira
Supervisor abroad: Marko Hyvonen
Instituição-sede : Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos, SP, Brazil
Local de pesquisa : University of Cambridge, England  
Associated to the scholarship:15/07005-3 - Structural Biology and Medicinal Chemistry studies toward the discovery and design of new agrochemicals, BP.DD

Abstract

Sugarcane derivatives stand out as major contributors to renewable energy sources in bioenergy production. However, the occurrence of severe diseases affects the productivity of sugarcane crops. One such condition is leaf scald disease, which is caused by the gram-negative bacteria Xanthomonas albilineans. Leaf scald disease has a dramatic impact on crop productivity, including reduced yields and reducing the quality of the juice. The absence of chemical or biological agents to treat the disease justifies research and the development of new bioactive molecules as effective and selective agrochemicals. An attractive metabolic pathway explored for this purpose is the biosynthesis of folates. Enzymes involved in synthesis and modification of folates are validated molecular targets for inhibitor design. In this context, the enzyme dihydropteroate synthase (XaDHPS) is essential for biosynthesis of folates and it has been selected for structural characterization and inhibitor discovery. Previous structural and functional characterization of XaDHPS carried out in our lab provides the basis for exploring the enzyme as a target for inhibitor screening and discovery. In this proposal, we will investigate the application of fragment-based drug discovery methods to explore diverse chemical scaffolds directed towards the discovery of XaDHPS inhibitors. The ligands identified by these strategies will be characterized by biophysical methods to better understand the molecular interactions. The most potent XaDHPS inhibitors will be assessed in vitro against X. albilineans. The successful outcomes of our multidisciplinary strategy may identify XaDHPS inhibitors as lead candidates for development and subsequent agrochemical use. (AU)