Antibacterial Activity of 1-Dodecylpyridinium Tetrafluoroborate and Its Inclusion Complex With Sulfobutyl Ether-β-Cyclodextrin Against MDR Acinetobacter baumannii Strains

Abstract

Background. The bacterial pathogen Acinetobacter baumannii is one of the most dangerous multi-drug-resistant (MDR) microorganisms, which causes numerous bacterial infections. Nowadays, there is an urgent need for new broad-spectrum antibacterial agents with specific molecular mechanisms of action. Long-chain 1-alkylpyridinium salts are efficient cationic biocides which can inhibit enzymes involved in the biosynthesis of bacterial fatty acids. Incorporating these compounds into inclusion complexes with cyclic oligosaccharide β-cyclodextrin can reduce their relatively high acute toxicity. Objective. The aim of this research was to develop new anti-A. baumannii agents based on hydrophobic 1-alkylpyridinium salt and its inclusion complex with sulfobutyl ether b-cyclodextrin (SBECD). Methods. Hydrophobic cationic biocide 1-dodecylpyridinium tetrafluoroborate (PyrC12-BF4) and its inclusion complex with SBECD have been synthesized. The structure of the SBECD/PyrC12-BF4 complex was characterized by 1H Nuclear Magnetic Resonance spectroscopy, as well as UV spectroscopy. In vitro antibacterial activity of the synthesized compounds was estimated against MDR clinical isolates of A. baumannii using standard disc diffusion method. Acute toxicity studies were performed on Daphnia magna model hydro­biont. Molecular docking was performed using the crystal structure of the A. baumannii 3-oxoacyl-[acyl-carrier-protein] reductase (FabG). Results. The results of 1H NMR study revealed the formation of an inclusion complex between SBECD and PyrC12-BF4. The cationic biocide demonstrated high activity against four tested antibiotic-resistant strains of A. baumannii, whereas the SBECD/PyrC12-BF4 complex was active against only two bacterial strains. Molecular docking of 1-dodecylpyridinium ligand into the active site of the A. baumannii (FabG) showed complex formation at an allosteric site located between subunits C, D. The acute toxicity (LC50) of PyrC12-BF4 and its inclusion complex was found to be 0.007 and 0.033 ml/g, respectively. Conclusions. Hydrophobic cationic biocide PyrC12-BF4 has high antibacterial activity against MDR A. baumannii. The inhibition of the active site FabG may be one of the possible mechanisms of anti-A. baumannii activity of the PyrC12-BF4. The SBECD/PyrC12-BF4 inclusion complex showed an almost 5-fold reduction in acute toxicity compared to PyrC12-BF4, while retaining activity against certain tested A. baumannii bacterial strains.

Keywords

• cationic biocide
• antibacterial activity
• acute toxicity
• molecular docking
• β-cyclodextrin
• inclusion complex