Concepción González-Bello
Universidad de Santiago de Compostela
Spain
Title: Covalent inhibition of bacterial type I dehydroquinase – Opportunities for anti-virulence therapies
Biography
Biography: Concepción González-Bello
Abstract
The loss of effectiveness of current antibiotics caused by the development of drug resistance, along with the evident decline in antibiotic research by the major pharmaceutical companies during the last 50 years, has triggered the search for novel antibiotics and alternative therapies. Targeting bacterial virulence is an attractive choice that is increasingly being explored. The inhibition of virulence factors will lead to a loss of the ability of bacteria to cause infection in the host and, as a consequence they could be more easily eliminated by the immune system. A promising target for the development of new anti-virulence agents is the type I dehydroquinase enzyme (EC 4.2.1.10, aroD gene, DHQ1). This enzyme does not have any counterpart in human cells and seems to act as a virulence factor in vivo as the deletion of the aroD gene has been proven to afford satisfactory live oral vaccines. In this talk, several irreversible inhibitors of this enzyme that cause the covalent modification of the DHQ1rnfrom Salmonella typhi and Staphylococcus aureus and that are able to reduce the ability of Salmonella enteritidis to kill A459rnrespiratory cells will be presented. The resolution of diverse crystal structures of DHQ1 from Salmonella Typhi chemically modified by those compounds, the detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism of those compounds. Our recent results on this project will be presented