Understanding the Origins of Bacterial Resistance to Aminoglycosides through Molecular Dynamics Mutational Study of the Ribosomal A-Site

The work is supported by the University of Warsaw (BST1450/2009 1550/2010 and G31-4), Polish Ministry of Science and Higher Education (N N301 245236 and N N301 033339) and Foundation for Polish Science (Focus program and Team project (TEAM/2009-3/8) co-financed by European Regional Development Fund operated within Innovative Economy Operational Programme). Work at UCSD is supported in part by National Science Foundation (NSF), National Institutes of Health, Howard Hughes Medical Institute, Center for Theoretical Biological Physics, National Biomedical Computation Resource, and the NSF Supercomputer Centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

In hospitals throughout the world, aminoglycosidic antibiotics are used to combat even the most severe bacterial infections. However, the continuous emergence of resistant bacteria has created an urgent need to improve these antibiotics. Aminoglycosides bind to bacterial ribosomal RNA. Experiments have shown that specific point mutations in the RNA confer high resistance against aminoglycosides in bacteria. We performed molecular dynamics simulations of the aminoglycosidic binding site model after introducing various mutations. Here, we show that even single nucleotide substitutions can significantly change the physicochemical features of the binding site. In addition, we hypothesize why certain mutations result in bacterial resistance to aminoglycosides.

Bartosz Brach