Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity

T. J. Young*, G. P. Oliver, D. Pryde, M. Perros and T. Parkinson

Discovery Biology, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK

Keywords: SSRI, serotonin, antifungal, cytotoxicity

Sir,

In two recent publications, Lass-Flörl et al.1,2 report that a number of selective serotonin reuptake inhibitors (SSRIs) exhibit fungicidal activity against a spectrum of medically important opportunistic fungal pathogens, including species of Candida and Aspergillus. This appears to be an exciting observation and is one we have investigated with interest because sertraline, a Pfizer SSRI, features in these articles.

SSRIs exert their pharmacological action through inhibition of the sodium-dependent serotonin transporter (5-HTT). The findings of Lass-Flörl et al.1,2 are intriguing, as there is no fungal orthologue of 5-HTT. It is therefore unlikely that SSRIs exert their antifungal activity through their known pharmacological target. To investigate this hypothesis, we selected sertraline, eight close analogues and three other marketed SSRIs to cover a wide range of potencies against 5-HTT and determined their MICs against a variety of fungi using NCCLS3 methods (Table 1). In agreement with Lass-Flörl et al.,1,2 sertraline displayed broad-spectrum antifungal activity (6.3–25 mg/L) and was also fungicidal against the panel of species tested (data not shown). Paroxetine and fluoxetine were also found to have antifungal activity, being most potent against the hypersusceptible Candida albicans strain DSY1204, which has a number of drug-efflux pumps deleted.4 However, we discovered that CP-51973, CP-50723 and CP-52002, the enantiomer and two diastereoisomers of sertraline, respectively, had essentially identical antifungal activity against the panel of species tested to sertraline itself, despite their reduced potency against 5-HTT. When analysed by the method of ordinary least squares (OLS) there was no significant correlation between the IC50 (half maximum inhibitory concentration) of the tested compounds against 5-HTT, and the MIC against fungal species (for instance, r2 = 0.12 for DSY1204). These data suggest that the antifungal activity of sertraline is unlikely to be a consequence of inhibiting 5-HTT.


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Table 1.  In vitro antifungal, cytotoxic and 5-HTT activity of sertraline, eight close analogues and other selected SSRIs
 
Interestingly, we observed a relationship between the antifungal potency of SSRIs and the degree of lipophilicity (OLS r2 = 0.57 between cLogP and MIC for DSY1204, where cLogP is the logarithm of the calculated partition coefficient between n-octanol and water), with the most potent antifungal compound being the most lipophilic. We often find that lipophilic compounds exhibit cytotoxic characteristics at high concentrations, a phenomenon also observed by others (e.g. Chen et al.5), suggesting that toxicity rather than a specific inhibitory mechanism may be driving the antifungal activity of SSRIs.

To investigate this hypothesis, we determined the cytotoxic activity of each compound following 72 h exposure to a human epithelial cell line, HeLa, using the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cell viability assay6 (Table 1, CC50 value). All compounds tested were cytotoxic at concentrations lower than their MIC. This apparent fungal resilience is a phenomenon we observe regularly for toxic compounds and can be attributed, at least in part, to the fungal cell wall and the activity of drug efflux pumps. Consistent with our hypothesis, we observed a good correlation between the CC50 (half maximum cytotoxic concentration) of SSRIs and their antifungal activity, with the most cytotoxic compounds having the most potent antifungal properties (OLS r2 = 0.62 for DSY1204). Furthermore, of particular significance to the conclusion of the present study was the similarity of the CC50s for sertraline, its enantiomer and two distereoisomers, which reflects their observed antifungal properties and suggests again a non-specific, toxic mechanism of action.

As discussed by Lass-Flörl et al.,1,2 sertraline reaches steady-state plasma levels of 50 µg/L, a concentration significantly lower than that required for antifungal activity. The present study indicates that the antifungal effect of SSRIs is mediated through a non-specific mechanism related to the lipophilicity of the agents, and is associated with significant toxic effects on human cells at concentrations required for activity against fungal pathogens. Therefore, based on the results of the present study, it is our opinion that SSRIs will neither prove useful chemotherapeutic mediators of opportunistic fungal infections nor provide useful leads for the development of more potent antifungal agents with a specific mechanism of action.

Footnotes

* *Corresponding author. Tel: +44-1304-644856; Fax: +44-1304-651819; E-mail: Tim_Young{at}Sandwich.Pfizer.com Back

References

1 . Lass-Flörl, C., Dierich, M. P., Fuchs, D., Semenitz, E. & Ledochowiski, M. (2001). Antifungal activity against Candida species of the selective serotonin reuptake inhibitor, sertraline. Clinical Infectious Diseases 33, E135–6.[CrossRef][Medline]

2 . Lass-Flörl, C., Dierich, M. P., Fuchs, D., Semenitz, E., Jenewein, I. & Ledochowiski, M. (2001). Antifungal properties of selective serotonin reuptake inhibitors against Aspergillus species in vitro. Journal of Antimicrobial Chemotherapy 48, 775–9.[Abstract/Free Full Text]

3 . National Committee for Clinical Laboratory Standards. (1995). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeast: Tentative Standard M27-A. NCCLS, Villanova, PA, USA.

4 . Marchetti, O., Majcherczyk, P. A., Glauser, M. P., Bille, J., Moreillon, P. & Sanglard, D. (2001). Sensitive bioassay for determination of fluconazole concentrations in plasma using a Candida albicans mutant hypersusceptible to azoles. Antimicrobial Agents and Chemotherapy 45, 696–700.[Abstract/Free Full Text]

5 . Chen, P., Cheng, P. T., Alam, M., Beyer, B. D., Bisacchi, G. S., Dejneka, T. et al. (1996). Aminodiol HIV protease inhibitors. Synthesis and structure–activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity. Journal of Medicinal Chemistry 39, 1991–2007.[CrossRef][ISI][Medline]

6 . Cory, A. H., Owen, T. C., Barltrop, J. A. & Cory J. G. (1991). Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Communications 3, 207–12.[ISI][Medline]

7 . Melleruo, E. T. & Plenge, P. (1986). High affinity binding of 3H-paroxetine and 3H-imipramine to rat neuronal membranes. Psychopharmacology 89, 436–9.[ISI][Medline]

8 . Sur, C., Betz, H. & Schloss, P. (1998). Distinct effects of imipramine on 5-hydroxytryptamine uptake mediated by recombinant rat serotonin transporter SERT1. Journal of Neurochemistry 70, 2545–53.[ISI][Medline]





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