engleski

Conformational Analysis of β-Lactamase Inhibitors

Due to the resistance, bacterial infections are now recognized as a major public health issue and an important social challenge.[1] Bacterial resistance to antibiotics cause a dramatic increase of mortality associated with infections, and also present an significant economic burden. β-lactam antibiotics belong to the class of antibiotics with a broad spectrum of activity (e.g. penicillin derivatives). The mechanism of their bactericidal action includes inhibition of enzymes involved in the cell wall synthesis. Unfortunately, efficiency of these important antibiotics is significantly reduced by bacterial β-lactamases. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors were introduced into clinical practice while the search for new ones is ongoing. These inhibitors greatly enhance the efficacy of β-lactam antibiotics in the treatment of serious infections. Conformational landscape of compounds reflects molecular properties including reactivity.[2] It is consisting of all possible conformations (including conformers that correspond to a distinct local potential energy minimum and bioactive conformations). In order to identify the most important parts of the conformational landscape responsible for the activity, a full conformational analysis for a set of known β- lactamase inhibitors as well as for the new quinuclidinium based compounds will be performed. This analysis includes systematic variations of torsional angles around single bonds in molecules and calculation of electronic energies providing surface written in the form of the n dimensional data. Combinatorial algorithm will be used to determine all local minima (conformers) from these multidimensional surfaces and sets of conformers including their relative abundance in vacuo and in solution will be presented. Figure 1: Conformational landscape of β- lactamase inhibitor sulbactam spanned by three torsional coordinates. References [1] C. T. Walsh, T. A. Wencewicz, J. Antibiot. 67 (2014) 7–22. [2] M. Majerić Elenkov, I. Primožič, T. Hrenar, A. Smolko, I. Dokli, B. Salopek-Sondi, L. Tang, Org. Biomol. Chem. 10 (2012) 5063– 5072.

β-laktamaze, inhibitori, konformacijski prostor

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