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.
- 1. University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 2. University of Split, Faculty of Science, Department of Biology, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 3. University of Split, Faculty of Science, Department of Physics, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 4. University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 5. University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 6. University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 7. University of Split, Faculty of Science, Department of Physics, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
- 8. University of Zagreb, Faculty of Science, Department of Chemistry, Horvatovac 102a, 10 000, Zagreb, Croatia. Electronic address: [email protected].
- 9. University of Split, Faculty of Science, Department of Chemistry, R. Boškovića 33, 21 000, Split, Croatia. Electronic address: [email protected].
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.