Photo: CDC
Publish Date: 27.12.2021
Category: Outstanding research achievements, Our contribution to sustainable development goals
Sustainable development goals: 4 Quality education (Indicators)
An international research team led by Prof. Marko Anderluh, PhD, from the Faculty of Pharmacy, University of Ljubljana, and Nikola Minovski, PhD, from the Institute of Chemistry has synthesised new molecules that signify a breakthrough in the treatment of infections with super-resistant bacteria.
In an article published in the journal Nature Communications, the authors (Anja Kolarič, Thomas Germe, PhD, Asst. Prof. Martina Hrast, PhD, Clare E. M. Stevenson, PhD, David M. Lawson, PhD, Nicolas P. Burton, PhD, Judit Vörös, PhD, Prof. Anthony Maxwell, PhD, sci. assoc. Nikola Minovski, PhD, Prof. Marko Anderluh, PhD) present the planning, synthesis and evaluation of novel bacterial type II topoisomerase inhibitors (NBTI), which stabilise the complex between the DNA molecule and the DNA gyrase enzyme. The obtained molecules have an extremely strong inhibitory action on an isolated DNA gyrase enzyme and consequently also very strong antibacterial activity, so they have been patent-protected.
The precise mechanism of action for NBTI was previously hypothetical, since earlier researchers imagined the possibility of creating a triple complex between a single-chain inoculated DNA and the DNA gyrase enzyme, which are linked by a NBTI molecule, but had been unable to prove it without a doubt.
The article presents the three-dimensional structure of the triple complex innovative molecule NBTI-DNA-DNA gyrase, as the first such structure where the aforementioned mechanism is clearly proven. The added value of the presented structure is evidence of the existence of a symmetrical split halogen bond in the biological environment. This type of halogen bond runs counter to the traditional interpretation, and previously had only been proven in crystal models of small molecules and not also in biological macromolecules. The proven symmetrical split halogen bonds can be used to advantage in planning new active ingredients for medications.
The editor of the Nature Communications journal specifically emphasised this article in the Editorial Highlights: https://www.nature.com/collections/wdzvyhgxft.
Author: Boris Oblak (Likovna produkcija, Boris Oblak, s. p.).
Source: Kolarič, A., Germe, T., Hrast, M. et al. Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds. Nat Commun 12, 150 (2021). https://doi.org/10.1038/s41467-020-20405-8