Targeting The Motion Of Shikimate Kinase-Opportunities For Antibiotic Drug Development | 62506
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The increasing development and spread of resistance to current antibiotics have turned ordinary bacterial infections into
illnesses that cannot be controlled. Infections from resistant bacteria are now too common and some pathogens have even
become resistant to multiple types of antibiotics. Therefore, it is urgent to search for new antibacterial agents and approaches
to face the challenge of multidrug resistance. The disruption of the growth cycle by preventing the synthesis and assembly of
key components of bacterial processes is the most widely used strategy to combat bacterial infections. Most current antibiotics
that are highly successful in human clinical use, surprisingly targeted at only four main key processes and resistance to these
antibiotics is widespread and well known. Therefore, the search for unexplored bacterial functions appears to be a good option
for the development of novel antimicrobial agents with a new mechanism of action. For this purpose, our research group is
studying the possible development of new antibiotics whose mode of action is based on the selective and effective inhibition of
an essential enzyme in bacteria that does not have any counterpart in human cells, shikimate kinase (SK). This enzyme is essential
in relevant pathogenic bacteria such as Mycobacterium tuberculosis, Helicobacter pylori and Pseudomonas aeruginosa. The
starting point for our inhibitors design was the study of: (a) the substrate binding requirements, (b) the phosphoryl-transfer
mechanism and (c) the essential enzyme motions for product release. Here we report results from NMR, biochemical, structural
and Molecular Dynamics simulation studies that help understand the catalytic mechanism, the binding requirements
and the essential enzyme motions for product release of the SK enzyme. Based on these results, potent reversible competitive
inhibitors of the enzyme were developed. An ester pro-drug approach was used for achieving good in vitro activities against H.
pylori. 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 Pre-doctoral stays in the University of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After a Post-doctoral stay in University of Cambridge (UK) with Prof. Abell, she joined USC as an Assistant Professor, was promoted to Associate Professor in 2003 and obtained the Spanish habilitation to full Professor in 2011. She joined the Center for Research in Biological Chemistry and Molecular Materials (CIQUS) as a Group Leader in 2011. She is author of more than 70 papers and several book chapters. She is a member of the ChemMedChem International Advisory Board and an Academic Editor of PLOS ONE. Her main research interest is to develop updated therapies targeting infectious diseases, in particular, drugs with new mechanisms of action to combat the growth of antibiotic-resistant bacteria.