Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex
2022
Аутори
Stevanović, Nevena Lj.Kljun, Jakob
Aleksić, Ivana
Škaro Bogojević, Sanja
Milivojević, Dušan
Veselinović, Aleksandar
Turel, Iztok
Djuran, Milos
Nikodinović-Runić, Jasmina
Glišić, Biljana
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1-7 of the general formula [AuCl3(azole)], where azole stands for imidazole (im, 1), 1-isopropylimidazole (ipim, 2), 1-phenylimidazole (phim, 3), clotrimazole (ctz, 4), econazole (ecz, 5), tioconazole (tcz, 6) and voriconazole (vcz, 7) were synthesized, characterized and biologically evaluated. In all complexes, the corresponding azole ligand is monodentately coordinated to the Au(III) via the imidazole or triazole nitrogen atom, while the remaining coordination sites are occupied by chloride anions leading to the square-planar arrangement. In vitro antimicrobial assays showed that the complexation of inactive azoles, imidazole, 1-isopropylimidazole and 1-phenylimidazole, to the Au(III) ion led to complexes 1-3, respectively, with moderate activity against the investigated strains and low cytotoxicity on the human normal lung fibroblast cell line (MRC-5). Moreover, gold(III) complexes 4-...7 with clinically used antifungal agents clotrimazole, econazole, tioconazole and voriconazole, respectively, have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole (6) and voriconazole (7). The complexes 4-7 and the corresponding antifungal azoles inhibited the growth of dermatophyte Microsporum canis at 50 and 25 mu g mL(-1). Gold(III) complexes 1-3 significantly reduced the amount of ergosterol in the cell membrane of Candida albicans at the subinhibitory concentration of 0.5 x MIC (minimal inhibitory concentration), while the corresponding imidazole ligands did not significantly affect the ergosterol content, indicating that the mechanism of action of the gold(III)-azole complexes is associated with inhibition of ergosterol biosynthesis. Finally, complexes 5 and 6 significantly reduced the production of pyocyanin, a virulence factor in Pseudomonas aeruginosa controlled by quorum sensing, and increased cell survival after exposure to this bacterium. These findings could be of importance for the development of novel gold(III)-based antivirulence therapeutic agents that attenuate virulence without pronounced effect on the growth of the pathogens, offering a lower risk for resistance development.
Извор:
Dalton Transactions, 2022, 51, 13, 5322-5334Издавач:
- Royal Soc Chemistry, Cambridge
Финансирање / пројекти:
- Slovenian Research Agency [P1-0175]
- Serbian Academy of Sciences and Arts [01-2019-F65, F128. N]
- Ministry of Education, Science and Sport of the Republic of Slovenia
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200122 (Универзитет у Крагујевцу, Природно-математички факултет) (RS-MESTD-inst-2020-200122)
DOI: 10.1039/d2dt00411a
ISSN: 1477-9226
PubMed: 35293926
WoS: 000769619100001
Scopus: 2-s2.0-85127759754
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Stevanović, Nevena Lj. AU - Kljun, Jakob AU - Aleksić, Ivana AU - Škaro Bogojević, Sanja AU - Milivojević, Dušan AU - Veselinović, Aleksandar AU - Turel, Iztok AU - Djuran, Milos AU - Nikodinović-Runić, Jasmina AU - Glišić, Biljana PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1568 AB - In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1-7 of the general formula [AuCl3(azole)], where azole stands for imidazole (im, 1), 1-isopropylimidazole (ipim, 2), 1-phenylimidazole (phim, 3), clotrimazole (ctz, 4), econazole (ecz, 5), tioconazole (tcz, 6) and voriconazole (vcz, 7) were synthesized, characterized and biologically evaluated. In all complexes, the corresponding azole ligand is monodentately coordinated to the Au(III) via the imidazole or triazole nitrogen atom, while the remaining coordination sites are occupied by chloride anions leading to the square-planar arrangement. In vitro antimicrobial assays showed that the complexation of inactive azoles, imidazole, 1-isopropylimidazole and 1-phenylimidazole, to the Au(III) ion led to complexes 1-3, respectively, with moderate activity against the investigated strains and low cytotoxicity on the human normal lung fibroblast cell line (MRC-5). Moreover, gold(III) complexes 4-7 with clinically used antifungal agents clotrimazole, econazole, tioconazole and voriconazole, respectively, have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole (6) and voriconazole (7). The complexes 4-7 and the corresponding antifungal azoles inhibited the growth of dermatophyte Microsporum canis at 50 and 25 mu g mL(-1). Gold(III) complexes 1-3 significantly reduced the amount of ergosterol in the cell membrane of Candida albicans at the subinhibitory concentration of 0.5 x MIC (minimal inhibitory concentration), while the corresponding imidazole ligands did not significantly affect the ergosterol content, indicating that the mechanism of action of the gold(III)-azole complexes is associated with inhibition of ergosterol biosynthesis. Finally, complexes 5 and 6 significantly reduced the production of pyocyanin, a virulence factor in Pseudomonas aeruginosa controlled by quorum sensing, and increased cell survival after exposure to this bacterium. These findings could be of importance for the development of novel gold(III)-based antivirulence therapeutic agents that attenuate virulence without pronounced effect on the growth of the pathogens, offering a lower risk for resistance development. PB - Royal Soc Chemistry, Cambridge T2 - Dalton Transactions T1 - Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex EP - 5334 IS - 13 SP - 5322 VL - 51 DO - 10.1039/d2dt00411a ER -
@article{ author = "Stevanović, Nevena Lj. and Kljun, Jakob and Aleksić, Ivana and Škaro Bogojević, Sanja and Milivojević, Dušan and Veselinović, Aleksandar and Turel, Iztok and Djuran, Milos and Nikodinović-Runić, Jasmina and Glišić, Biljana", year = "2022", abstract = "In a search for novel antimicrobial metal-based therapeutic agents, mononuclear gold(III) complexes 1-7 of the general formula [AuCl3(azole)], where azole stands for imidazole (im, 1), 1-isopropylimidazole (ipim, 2), 1-phenylimidazole (phim, 3), clotrimazole (ctz, 4), econazole (ecz, 5), tioconazole (tcz, 6) and voriconazole (vcz, 7) were synthesized, characterized and biologically evaluated. In all complexes, the corresponding azole ligand is monodentately coordinated to the Au(III) via the imidazole or triazole nitrogen atom, while the remaining coordination sites are occupied by chloride anions leading to the square-planar arrangement. In vitro antimicrobial assays showed that the complexation of inactive azoles, imidazole, 1-isopropylimidazole and 1-phenylimidazole, to the Au(III) ion led to complexes 1-3, respectively, with moderate activity against the investigated strains and low cytotoxicity on the human normal lung fibroblast cell line (MRC-5). Moreover, gold(III) complexes 4-7 with clinically used antifungal agents clotrimazole, econazole, tioconazole and voriconazole, respectively, have, in most cases, enhanced antimicrobial effectiveness relative to the corresponding azoles, with the best improvement achieved after complexation of tioconazole (6) and voriconazole (7). The complexes 4-7 and the corresponding antifungal azoles inhibited the growth of dermatophyte Microsporum canis at 50 and 25 mu g mL(-1). Gold(III) complexes 1-3 significantly reduced the amount of ergosterol in the cell membrane of Candida albicans at the subinhibitory concentration of 0.5 x MIC (minimal inhibitory concentration), while the corresponding imidazole ligands did not significantly affect the ergosterol content, indicating that the mechanism of action of the gold(III)-azole complexes is associated with inhibition of ergosterol biosynthesis. Finally, complexes 5 and 6 significantly reduced the production of pyocyanin, a virulence factor in Pseudomonas aeruginosa controlled by quorum sensing, and increased cell survival after exposure to this bacterium. These findings could be of importance for the development of novel gold(III)-based antivirulence therapeutic agents that attenuate virulence without pronounced effect on the growth of the pathogens, offering a lower risk for resistance development.", publisher = "Royal Soc Chemistry, Cambridge", journal = "Dalton Transactions", title = "Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex", pages = "5334-5322", number = "13", volume = "51", doi = "10.1039/d2dt00411a" }
Stevanović, N. Lj., Kljun, J., Aleksić, I., Škaro Bogojević, S., Milivojević, D., Veselinović, A., Turel, I., Djuran, M., Nikodinović-Runić, J.,& Glišić, B.. (2022). Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex. in Dalton Transactions Royal Soc Chemistry, Cambridge., 51(13), 5322-5334. https://doi.org/10.1039/d2dt00411a
Stevanović NL, Kljun J, Aleksić I, Škaro Bogojević S, Milivojević D, Veselinović A, Turel I, Djuran M, Nikodinović-Runić J, Glišić B. Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex. in Dalton Transactions. 2022;51(13):5322-5334. doi:10.1039/d2dt00411a .
Stevanović, Nevena Lj., Kljun, Jakob, Aleksić, Ivana, Škaro Bogojević, Sanja, Milivojević, Dušan, Veselinović, Aleksandar, Turel, Iztok, Djuran, Milos, Nikodinović-Runić, Jasmina, Glišić, Biljana, "Clinically used antifungal azoles as ligands for gold(III) complexes: the influence of the Au(III) ion on the antimicrobial activity of the complex" in Dalton Transactions, 51, no. 13 (2022):5322-5334, https://doi.org/10.1039/d2dt00411a . .