The Influence of Lipid Matrix Composition on the Microenvironment of Levofloxacin in Liposomal Forms.

We have studied the interaction of the antibacterial drug levofloxacin with lipid bilayers of various compositions: 100% DPPC and with the addition of 20% cardiolipin. For DPPC liposomes, levofloxacin was found to penetrate into the subpolar region at the lipid-water interface. The role of the anionic lipid in the interaction of an active molecule with a bilayer has been established: levofloxacin enters the microenvironment of the phosphate group, displacing water, and does not penetrate into the hydrophobic part of the bilayer. For the first time, the study of the microenvironment of levofloxacin in the liposome by IR and CD spectroscopy was carried out. Such an approach based on a combination of several spectral methods opens up new prospects for the creation of new medicinal properties and the possibility of predicting the nature of the interaction of active molecules with biomembranes in order to predict their efficacy and potential side effects.

Novel non-ß-lactam inhibitor of ß-lactamase TEM-171 based on acylated phenoxyaniline.

The microbial resistance to antibiotics is a genuine global threat. Consequently, a search of new inhibitors remains of acute importance due to the increasing spread of multidrug resistance. Here we present a new type of non-ß-lactam ß-lactamase inhibitor PA-34 based on natural phenoxyaniline, identified using computer-assisted screening of scaffolds related to those of known low-affinity inhibitors. The compound displays reversible competitive inhibition of bacterial ß-lactamase TEM-171, with a Ki of 88 µM. Using enzyme kinetics, infra-red spectroscopy, fluorescence quenching and computer docking, we propose that the inhibitor binds at the entrance to the enzyme active site. This is a novel inhibition mechanism compared to binding covalently to the catalytic serine in the active site or non-covalently to the allosteric site. The residues involved in binding the inhibitor are conserved among molecular class A ß-lactamases. The identified compound and its proposed binding mode may have a potential for a regulation of the catalytic activity of a wide range of class A ß-lactamases. We also hypothesise that the presented route for finding non-ß-lactam compounds may be an effective and durable approach for combating bacterial antibiotic resistance.