Discovery of ligands as Xanthomonas albilineans dihydropteroate synthase inhibitors

• Grant number: 17/17816-4
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: January 23, 2018
• End date: January 22, 2019
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Andrew Albert de Oliveira
• Supervisor: Marko Hyvonen
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Institution abroad: 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)