The cover image of Biophysical Journal (Volume 108, Issue 3) shows how 12 different aminoglycoside antibiotics are bound to their RNA target of the bacterial ribosome. The superposition of the crystal structures demonstrates that two aminoglycoside rings maintain the same position in all complexes, which confirms that these rings form a scaffold for all aminoglycosides. These aminoglycosides restrict two adenines in a flipped-out position (nucleobases on the right side of the image), which is related to their antibacterial action, because proper dynamics of these adenines assures the fidelity of bacterial protein synthesis. This image was created to compare known aminoglycoside binding modes and their electrostatic interactions with this bacterial RNA target, which helped us propose aminoglycoside modifications.
Aminoglycosides are mainly used to cure infections caused by aerobic Gram-negative and selected Gram-positive bacteria. They are usually injected because their oral absorption is poor. In small concentrations they are also used in eye-drops and ointments. The application of higher doses of aminoglycosides is currently restricted to severe cases due to their ototoxicity and nephrotoxicity, as well as to reduce the growing bacterial resistance against these antibiotics. The main resistance mechanism is related to their chemical modification by bacterial aminoglycoside-modifying enzymes.
Finding new modifications of existing natural and semi-synthetic aminoglycosides could help overcome the resistance and toxicity problems. It would be desirable to modify aminoglycosides to increase their specificity toward pathogenic bacterial ribosomes and to minimize their affinity toward human ribosomes. This is the long-standing aim of our research. Based on electrostatic comparison of many aminoglycoside-RNA complexes, we selected aminoglycoside groups that could be modified so that the antibiotics have more affinity with the bacterial RNA target. Proposed modifications, if possible to achieve, should diminish both toxicity and susceptibility to aminoglycoside-modifying enzymes.
For more information about our research please visit the website of Biomolecular Machines Laboratory: http://bionano.cent.uw.edu.pl/Research
The LSDB program used in our computations can be downloaded from the website: http://crystal.chem.uw.edu.pl/software.html
– Marta Kulik, Anna M. Goral, Maciej Jasiński, Paulina M. Dominiak, and Joanna Trylska