Covalent Inhibition Of Bacterial Type I Dehydroquinase – Opportunities For Anti-virulence Therapies | 39348
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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 18.104.22.168, 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 DHQ1
from Salmonella typhi and Staphylococcus aureus and that are able to reduce the ability of Salmonella enteritidis to kill A459
respiratory 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.
Concepción González-Bello has obtained her PhD at the University of Santiago de Compostela (USC, Spain) in 1994. She did two predoctoral stays in the University of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After a postdoctoral stay in the University of Cambridge (UK) with Prof. Abell, she joined USC as an Assistant Professor, and was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to full Professor in 2011. In 2011, she joined the CIQUS, a new USC research center, as a group leader. She is author of about 70 papers and several patents and book chapters.