The Antidepressant Sertraline Induces the Formation of Supersized Lipid Droplets in the Human Pathogen Cryptococcus neoformans

Abstract

The prevalence and increasing incidence of fungal infections globally is a significant worldwide health problem. Cryptococcosis, primarily caused by the pathogenic yeast Cryptococcus neoformans, is responsible for approximately 181,000 estimated deaths annually. The scarcity of treatments and the increasing resistance to current therapeutics highlight the need for the development of antifungal agents which have novel mechanisms of action and are suitable for clinical use. Repurposing existing FDA-approved compounds as antimycotic therapeutics is a promising strategy for the rapid development of such new treatments. Sertraline (SRT), a commonly prescribed antidepressant, is a broad-spectrum antifungal agent with particular efficacy against C. neoformans. However, the effect of SRT on fungal physiology is not understood. Here, we report that SRT induces the formation of supersized lipid droplets (SLDs) in C. neoformans, and in Candida albicans, Saccharomyces cerevisiae, and Aspergillus fumigatus. SLDs were not induced in C. neoformans by treatment with the antifungal fluconazole (FLC), consistent with SRT and FLC acting differently to perturb C. neoformans physiology. The formation of SLDs in response to SRT indicates that this compound alters the lipid metabolism of C. neoformans. Moreover, the SRT-induced enlargement of LDs in other fungal species may indicate a common fungal response to SRT.

The Antidepressant Sertraline Affects Cell Signaling and Metabolism in Trichophyton rubrum

“…In vitro and in vivo studies have demonstrated its potential application in treating osteomyelitis infection [ 38 ] and cancer [ 39 ]. Furthermore, SRT presents antiparasitic [ 40 ], antibacterial [ 41 ], and antifungal activities against various pathogenic fungi, including C. neoformans [ 10 , 11 ], Aspergillus fumigatus [ 7 ], Trichosporon asahii [ 12 ], Sporothrix schenckii [ 9 ], and T. rubrum [ 15 ]. Through a drug repurposing approach, novel therapeutic options can rapidly enter clinical practice, as their safety and pharmacokinetics have been validated previously in patients.…”

“…Numerous drugs used to treat non-infectious conditions such as inflammation, cardiovascular diseases, or depression are known to exhibit antimicrobial activities. The selective serotonin reuptake inhibitor (SSRI) sertraline (SRT), commonly used as an antidepressant, was revealed to have antifungal activity [ 7 , 8 , 9 , 10 ]. Furthermore, this drug interacts synergistically in vitro with antifungals such as azoles, caspofungin, and amphotericin B, indicating its potential use as an adjuvant in treating fungal infections [ 11 , 12 , 13 , 14 , 15 ].…”

“…It has been proposed that SRT intercalates into the phospholipid membranes of V-ATPase-acidified organelles [ 18 ]. Moreover, it is possible that the potent antifungal activity against Cryptococcus neoformans could also be driven by the inhibition of protein synthesis and/or other actions interfering with lipid metabolism [ 10 , 11 ].…”

Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health

“…However, a few putative mechanisms have been suggested, including cell death mediated by the insertion of sertraline into the phospholipid membrane layers of intracellular organelles, 88 inhibition of ergosterol synthesis through sertraline binding to lanosterol 14-demethylase (CYP51) protein, 89 and alterations in the lipid metabolism. 90 Sertraline was clinically tested as an adjunctive antifungal therapy in HIV-infected individuals with cryptococcal meningitis. 91 Antifungal treatment using sertraline as an adjuvant resulted in faster cryptococcal cerebrospinal fluid clearance with decreased relapse.…”

Synergism between the Antidepressant Sertraline and Caspofungin as an Approach to Minimise the Virulence and Resistance in the Dermatophyte Trichophyton rubrum

“…Notably, combining SRT with itraconazole was also synergistic [ 16 ]. Essays on Cryptococcus neoformans evidenced the antifungal activity of SRT, either in monotherapy or in synergic combination with fluconazole [ 16 , 17 ]. In addition, SRT exhibited synergistic effects against Trichosporon asahii planktonic cells with caspofungin (CASP) [ 18 ].…”