Computer-guided identification of inhibitors against staphylococcal exfoliative toxins

• Grant number: 22/03901-8
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: December 01, 2022
• End date: November 29, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Raghuvir Krishnaswamy Arni
• Grantee: Jorge Enrique Hernández González
• Supervisor: Johannes Kirchmair
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
• Institution abroad: University of Vienna, Austria
• Associated to the scholarship: 20/10214-1 - Integrated computational and experimental strategies for the inhibition of exfoliative toxins from Staphylococcus aureus, BP.PD

Abstract

Several Staphylococcus spp. express exfoliative toxins (ETs), which act as key virulence factors facilitating host invasion and infection. S. aureus is a notorious pathogen that can produce different ETs (ETA to ETE) causing serious diseases in humans and animals of economic value, such as the staphylococcal scalded skin syndrome (SSSS) and mastitis. Other species, e.g., S. sciuri and S. hyicus, can produce a toxin termed ExhC, which causes exudative epidermitis (EE) in newborn pigs and cell necrosis in vitro. Most known ETs are glutamyl endopeptidases (GEPs) that cleave desmoglein-1 (Dsg-1), a skin protein critical for cell-cell adhesion. In general, ETs possess a very fine-tuned substrate specificity and are likely to require activation to attain full catalytic activity upon interaction via an exosite with a specific region of Dsg-1. In this proposed study we aim to discover new inhibitors of ETA, ETE and ExhC using state-of-the-art in silico approaches. More specifically, we will employ pharmacophore-based techniques and docking approaches to screen large collections of commercially available, drug-like compounds for substances that are likely to bind to the active and necrosis-linked sites of the ETs and, hence, inhibit the exfoliative/necrotic activity of those enzymes. Molecular dynamics (MD) simulations will be conducted to address the flexibility of the ligand binding sites. Moreover, we will use in silico tools to design or modify known peptide substrates of ETs in order to turn them into potent inhibitors. The best candidate substances will be purchased and evaluated in vitro for their inhibitory activity against the selected targets. (AU)