Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific 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 NCCLS 3 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 IC 50 (half maximum inhibitory concentration) of the tested compounds against 5-HTT, and the MIC against fungal species (for instance, r 2 = 0.12 for DSY1204). These data suggest that the antifungal activity of sertraline is unlikely to be a consequence of inhibiting 5-HTT. Interestingly, we observed a relationship between the anti-fungal potency of SSRIs and the degree of lipophilicity (OLS r 2 = 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 cyto-toxic activity of each …