Discovery of novel quaternary ammonium compounds based on quinuclidine-3-ol as new potential antimicrobial candidates

Eur J Med Chem. 2019 Feb 1:163:626-635. doi: 10.1016/j.ejmech.2018.12.023.

Linda Bazina ¹, Ana Maravić ², Lucija Krce ³, Barbara Soldo ⁴, Renata Odžak ⁵, Viljemka Bučević Popović ⁶, Ivica Aviani ⁷, Ines Primožič ⁸, Matilda Šprung ⁹

Affiliations

1 University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: linbaz@pmfst.hr.
2 University of Split, Faculty of Science, Department of Biology, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: amaravic@pmfst.hr.
3 University of Split, Faculty of Science, Department of Physics, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: lkrce@pmfst.hr.
4 University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: barbara@pmfst.hr.
5 University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: rodzak@pmfst.hr.
6 University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: viljemka@pmfst.hr.
7 University of Split, Faculty of Science, Department of Physics, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: iaviani@pmfst.hr.
8 University of Zagreb, Faculty of Science, Department of Chemistry, Horvatovac 102a, 10 000, Zagreb, Croatia. Electronic address: ines.primozic@chem.pmf.hr.
9 University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: msprung@pmfst.hr.

PMID: 30562698 DOI: 10.1016/j.ejmech.2018.12.023

Abstract

Quaternary ammonium compounds (QACs) are amphiphilic molecules displaying a broad-spectrum of Antibacterial activity. QACs are commonly used antiseptics in industrial, home and hospital settings. Given the emergence of the QAC-resistant bacteria, there is an urgent need to design new QACs with good antimicrobial activity, able to escape the host resistance mechanism. Therefore, a series of QACs derived from quinuclidine-3-ol and an alkyl chain of variable length (QOH-C3 to -C14), was designed and synthesized. The antimicrobial potential of the new monoquaternary QACs was surveyed against seventeen strains of emerging food spoilage and pathogenic Microorganisms, including clinical multidrug-resistant ESKAPE isolates. The QOH-C14 proved to have the strongest antimicrobial activity. It was highly active against all pathogens tested, particularly against the Gram-positive bacteria with minimal inhibitory concentrations (MICs) ranging from 0.06 to 3.9 μg/mL, and fungi exerting the MIC₉₀ between 0.12 and 3.9 μg/mL. The potency of QOH-C14, confirmed that alkyl chains are an important part of the structure with their lengths playing a critical role in bioactivity of these compounds. The atomic force microscopy images show the disruption of a cell membrane upon the treatment with QOH-C14. These results were additionally confirmed by flow cytometry and fluorescence microscopy. A relatively low toxicity toward healthy human cells underline that QOH-C14 has a potential as new QAC antimicrobial candidate.

Keywords

Antimicrobial activity; Cytotoxicity; Quaternary ammonium compounds; Quinuclidine.

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