INTEGRATED TRANSCRIPTOMIC PROFILING OF THE Candida albicans RESPONSE TO THE SYNERGISTIC INTERACTION BETWEEN ATOMOXETINE AND FLUCONAZOLE
Yıl 2026,
Cilt: 15 Sayı: 1, 32 - 45, 27.01.2026
Emilia Qomi Ekenel
,
Benjamin Kreka
,
Handan Açelya Kapkaç
,
Hülya Karaca Atsaros
Öz
Candida species are notorious opportunistic pathogens that can cause severe infections, especially in immunocompromised and medically vulnerable patients. Despite the availability of various antifungal drugs, their efficacy is often limited by drug toxicity and antifungal resistance. Therefore, repurposing existing clinically approved drugs is a promising approach to addressing this challenge. In this study, we investigated the potential synergistic effects of combining the antidepressant atomoxetine (ATMX) with the antifungal agent fluconazole (FLC) against Candida albicans. Our results demonstrated that ATMX (31.25 μg/mL) and FLC (1.95 μg/mL) exhibited a trend toward synergistic activity C. albicans. We performed RNA-Seq analysis to investigate the transcriptional response of C. albicans treated with ATMX-FLC combination. Our analysis indicated that the combination has a significant impact on ribosome biogenesis, secondary metabolite biosynthesis, and metabolic pathways. Overall, our findings highlight the potential of repurposing clinically approved drugs as a novel therapeutic strategy for the treatment of Candida infections, which continue to pose a significant global public health challenge.
Destekleyen Kurum
Anadolu Üniversitesi
Proje Numarası
1607S576 - 2008S091
Kaynakça
-
[1] Alves R, Barata-Antunes C, Casal M, Brown AJP, Van Dijk P, Paiva S. Adapting to survive: How Candida overcomes host-imposed constraints during human colonization. Plos Pathog, 2020;21:16(5).
-
[2] Romo JA, Zhang H, Cai H, Kadosh D, Koehler JR, Saville SP. Global transcriptomic analysis of the Candida albicans response to treatment with a novel inhibitor of filamentation. mSphere 2019;4(5): e00620-19.
-
[3] Khan MS, Malik A, Ahmad I. Anti-candidal activity of essential oils alone and in combination with amphotericin B or fluconazole against multi-drug resistant isolates of Candida albicans. Med Mycol, 2012;50(1):33-42.
-
[4] Oliveira AS, Martinez-de-Oliveira J, Donders GGG, Palmeira-de-Oliveira R, Palmeira-de-Oliveira A. Anti-Candida activity of antidepressants sertraline and fluoxetine: effect upon pre-formed biofilms. Med Microbiol Immunol, 2018;207:195-200.
-
[5] Gowri M, Jayashree B, Jeyakanthan J, Girija EK. Sertraline as a promising antifungal agent: inhibition of growth and biofilm of Candida auris with special focus on the mechanism of action in vitro. J Appl Microbiol, 2020;128(2):426-437.
-
[6] Lass-Flörl C, Dierich MP, Fuhs D, Semenitz E, Jenewein I, Ledochowski M. Antifungal properties of seletive serotonin reuuptake inhibitors against Aspergillus species in vitro. J Antimicrob Chemother, 2001;48:775-779.
-
[7] Munoz-Bellido JL, Munoz-Riado S, Garcia-Rodriguez JA. Antimicrobial ativity of psyhotropi drugs seletive serotonin reuptake inhibitors. Int J Antimicrob Agents, 2000;14:177-180.
-
[8] Mdarhri HA, Benmessaoud R, Yacoubi H, Seffar L, Assimi HG, Hamam M, Bouussettine R, Filali-Ansari N, Lahlou FA, Iawara I, Ennaji MM, Kettani-Halabi M. Alternatives therapeutic approaches to conventional antibiotics: Advantages, limitations and potential application in medicine. Antibiotics, 2022;11(12):1826.
-
[9] National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved Standard. Second edition, document M27-A2. 2002. National Committee for Clinical Laboratory Standards, Wayne, PA.
-
[10] Bellio P, Fagnani L, Nazzicone L, Celenza G. New and simplified method for drug combination studies by checkerboard assay. MethodsX 2021;8:101543.
-
[11] Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res, 2023;51:D587-D592.
-
[12] Spitzer M, Griffiths E, Blakely KM, Wildenhain J, Ejim L, Rossi L, et al. Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol Syst Biol., 2011;7:499.
-
[13] Zhai B, Zhou H, Yang L, Zhang J, Jung K, Giam CZ, et al. Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect. J Antimicrob Chemother, 2012;67(1):246–253.
-
[14] Vila T, Ishida K, Seabra SH, Rozental S, Lopez-Ribot JL. Candida albicans biofilm inhibition by sulfonamide derivatives of NSAIDs. Antimicrob Agents Chemother, 2016;60(6):3681–3689.
-
[15] Rueda C, Cuenca-Estrella M, Zaragoza Ó. Antifungal activity of antidepressants: what do we know and what are the mechanisms? J Fungi, 2020;6(4):336.
-
[16] Coleman ST, Fang TK, Rovinsky SA, Turano FJ, Moye-Rowley WS. Expression of a glutamate decarboxylase homologue is required for resistance to oxidative stress in Saccharomyces cerevisiae. J Biol Chem, 2001;276(8):244–248.
-
[17] Kamei, Y, Tamura T, Yoshida R, Ohta S, Fukusaki E, Mukai Y. GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomyces cerevisiae. Biochem Biophys Res Commun 2011;407(1):185-90.
-
[18] Costa C, Dias PJ, Sá-Correia I, Teixeira MC. MFS multidrug transporters in pathogenic fungi: Do they have real clinical impact? Front Physiol. 2019;10:730.
-
[19] Skrzypek MS, Binkley J, Binkley G, Miyasato SR, Simison M, Sherlock G. Candida Genome Database 2017; http://www.candidagenome.org/.
-
[20] Zhao L, Zhang X, Xu W, Wang L, Huang Y. Mechanisms of azole resistance and strategies to overcome it in Candida albicans. Front Microbiol, 2023;14:1111130.
-
[21] Zhang C, Liu X, Li S, Wang H. Transcriptional responses of Sclerotinia sclerotiorum to lipopeptide-induced stress. Fungal Biol, 2022;126(9):725–733.
-
[22] Yang X, Zhang L, Xiang Y, Du Lei, Huang X, Liu Y. Comparative transcriptome analysis of Sclerotinia sclerotiorum revealed its response mechanisms to the biological control agent, Bacillus amyloliquefaciens. Sci Rep, 2020;10:12576.
-
[23] Oliveira MM, Gonçalves T, Santos C, Lima N. Fluoxetine and sertraline as promising antifungal agents: A focus on Candida spp. J Mycol Med. 2015;25(2):128–134.
-
[24] Oliveira AS, Gaspar A, Palmeira-de-Oliveira R, Martinez-de-Oliveira J, Palmeira-de-Oliveira A. Anti-Candida activity of Fluoxetine alone and combined with Fluconazole: A synergistic action against Fluconazole-resistant strains. ASM 2014;58(7):4224-4226.
INTEGRATED TRANSCRIPTOMIC PROFILING OF THE Candida albicans RESPONSE TO THE SYNERGISTIC INTERACTION BETWEEN ATOMOXETINE AND FLUCONAZOLE
Yıl 2026,
Cilt: 15 Sayı: 1, 32 - 45, 27.01.2026
Emilia Qomi Ekenel
,
Benjamin Kreka
,
Handan Açelya Kapkaç
,
Hülya Karaca Atsaros
Öz
Candida species are notorious opportunistic pathogens that can cause severe infections, especially in immunocompromised and medically vulnerable patients. Despite the availability of various antifungal drugs, their efficacy is often limited by drug toxicity and antifungal resistance. Therefore, repurposing existing clinically approved drugs is a promising approach to addressing this challenge. In this study, we investigated the potential synergistic effects of combining the antidepressant atomoxetine (ATMX) with the antifungal agent fluconazole (FLC) against Candida albicans. Our results demonstrated that ATMX (31.25 μg/mL) and FLC (1.95 μg/mL) exhibited a trend toward synergistic activity C. albicans. We performed RNA-Seq analysis to investigate the transcriptional response of C. albicans treated with ATMX-FLC combination. Our analysis indicated that the combination has a significant impact on ribosome biogenesis, secondary metabolite biosynthesis, and metabolic pathways. Overall, our findings highlight the potential of repurposing clinically approved drugs as a novel therapeutic strategy for the treatment of Candida infections, which continue to pose a significant global public health challenge.
Proje Numarası
1607S576 - 2008S091
Kaynakça
-
[1] Alves R, Barata-Antunes C, Casal M, Brown AJP, Van Dijk P, Paiva S. Adapting to survive: How Candida overcomes host-imposed constraints during human colonization. Plos Pathog, 2020;21:16(5).
-
[2] Romo JA, Zhang H, Cai H, Kadosh D, Koehler JR, Saville SP. Global transcriptomic analysis of the Candida albicans response to treatment with a novel inhibitor of filamentation. mSphere 2019;4(5): e00620-19.
-
[3] Khan MS, Malik A, Ahmad I. Anti-candidal activity of essential oils alone and in combination with amphotericin B or fluconazole against multi-drug resistant isolates of Candida albicans. Med Mycol, 2012;50(1):33-42.
-
[4] Oliveira AS, Martinez-de-Oliveira J, Donders GGG, Palmeira-de-Oliveira R, Palmeira-de-Oliveira A. Anti-Candida activity of antidepressants sertraline and fluoxetine: effect upon pre-formed biofilms. Med Microbiol Immunol, 2018;207:195-200.
-
[5] Gowri M, Jayashree B, Jeyakanthan J, Girija EK. Sertraline as a promising antifungal agent: inhibition of growth and biofilm of Candida auris with special focus on the mechanism of action in vitro. J Appl Microbiol, 2020;128(2):426-437.
-
[6] Lass-Flörl C, Dierich MP, Fuhs D, Semenitz E, Jenewein I, Ledochowski M. Antifungal properties of seletive serotonin reuuptake inhibitors against Aspergillus species in vitro. J Antimicrob Chemother, 2001;48:775-779.
-
[7] Munoz-Bellido JL, Munoz-Riado S, Garcia-Rodriguez JA. Antimicrobial ativity of psyhotropi drugs seletive serotonin reuptake inhibitors. Int J Antimicrob Agents, 2000;14:177-180.
-
[8] Mdarhri HA, Benmessaoud R, Yacoubi H, Seffar L, Assimi HG, Hamam M, Bouussettine R, Filali-Ansari N, Lahlou FA, Iawara I, Ennaji MM, Kettani-Halabi M. Alternatives therapeutic approaches to conventional antibiotics: Advantages, limitations and potential application in medicine. Antibiotics, 2022;11(12):1826.
-
[9] National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved Standard. Second edition, document M27-A2. 2002. National Committee for Clinical Laboratory Standards, Wayne, PA.
-
[10] Bellio P, Fagnani L, Nazzicone L, Celenza G. New and simplified method for drug combination studies by checkerboard assay. MethodsX 2021;8:101543.
-
[11] Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro-Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res, 2023;51:D587-D592.
-
[12] Spitzer M, Griffiths E, Blakely KM, Wildenhain J, Ejim L, Rossi L, et al. Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol Syst Biol., 2011;7:499.
-
[13] Zhai B, Zhou H, Yang L, Zhang J, Jung K, Giam CZ, et al. Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect. J Antimicrob Chemother, 2012;67(1):246–253.
-
[14] Vila T, Ishida K, Seabra SH, Rozental S, Lopez-Ribot JL. Candida albicans biofilm inhibition by sulfonamide derivatives of NSAIDs. Antimicrob Agents Chemother, 2016;60(6):3681–3689.
-
[15] Rueda C, Cuenca-Estrella M, Zaragoza Ó. Antifungal activity of antidepressants: what do we know and what are the mechanisms? J Fungi, 2020;6(4):336.
-
[16] Coleman ST, Fang TK, Rovinsky SA, Turano FJ, Moye-Rowley WS. Expression of a glutamate decarboxylase homologue is required for resistance to oxidative stress in Saccharomyces cerevisiae. J Biol Chem, 2001;276(8):244–248.
-
[17] Kamei, Y, Tamura T, Yoshida R, Ohta S, Fukusaki E, Mukai Y. GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomyces cerevisiae. Biochem Biophys Res Commun 2011;407(1):185-90.
-
[18] Costa C, Dias PJ, Sá-Correia I, Teixeira MC. MFS multidrug transporters in pathogenic fungi: Do they have real clinical impact? Front Physiol. 2019;10:730.
-
[19] Skrzypek MS, Binkley J, Binkley G, Miyasato SR, Simison M, Sherlock G. Candida Genome Database 2017; http://www.candidagenome.org/.
-
[20] Zhao L, Zhang X, Xu W, Wang L, Huang Y. Mechanisms of azole resistance and strategies to overcome it in Candida albicans. Front Microbiol, 2023;14:1111130.
-
[21] Zhang C, Liu X, Li S, Wang H. Transcriptional responses of Sclerotinia sclerotiorum to lipopeptide-induced stress. Fungal Biol, 2022;126(9):725–733.
-
[22] Yang X, Zhang L, Xiang Y, Du Lei, Huang X, Liu Y. Comparative transcriptome analysis of Sclerotinia sclerotiorum revealed its response mechanisms to the biological control agent, Bacillus amyloliquefaciens. Sci Rep, 2020;10:12576.
-
[23] Oliveira MM, Gonçalves T, Santos C, Lima N. Fluoxetine and sertraline as promising antifungal agents: A focus on Candida spp. J Mycol Med. 2015;25(2):128–134.
-
[24] Oliveira AS, Gaspar A, Palmeira-de-Oliveira R, Martinez-de-Oliveira J, Palmeira-de-Oliveira A. Anti-Candida activity of Fluoxetine alone and combined with Fluconazole: A synergistic action against Fluconazole-resistant strains. ASM 2014;58(7):4224-4226.