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

Abstract

Trichophyton rubrum is responsible for several superficial human mycoses. Novel strategies aimed at controlling this pathogen are being investigated. The objective of this study was to evaluate the antifungal activity of the antidepressant sertraline (SRT), either alone or in combination with caspofungin (CASP). We calculated the minimum inhibitory concentrations of SRT and CASP against T. rubrum. Interactions between SRT and CASP were evaluated using a broth microdilution chequerboard. We assessed the differential expression of T. rubrum cultivated in the presence of SRT or combinations of SRT and CASP. We used MTT and violet crystal assays to compare the effect of SRT alone on T. rubrum biofilms with that of the synergistic combination of SRT and CASP. A human nail infection assay was performed. SRT alone, or in combination with CASP, exhibited antifungal activity against T. rubrum. SRT targets genes involved in the biosyntheses of cell wall and ergosterol. Furthermore, the metabolic activity of the T. rubrum biofilm and its biomass were affected by SRT and the combination of SRT and CASP. SRT alone, or in combination, shows potential as an approach to minimise resistance and reduce virulence.

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.…”

“…Through a drug repurposing approach, novel therapeutic options can rapidly enter clinical practice, as their safety and pharmacokinetics have been validated previously in patients. SRT is also effective alone or as an adjuvant therapeutic agent against fungal biofilm formation in vitro [ 15 ]. The synergistic effects of SRT combined with antifungals such as amphotericin B, caspofungin, or fluconazole have been documented in vitro [ 11 , 12 , 13 , 15 ].…”

“…We estimated the conidial concentration by counting in a Neubauer chamber. Approximately 1 × 10 6 conidia were inoculated into 100 mL Sabouraud dextrose broth (SDB; 2% ( w/v ) glucose, 1% ( w/v ) peptone) and incubated with agitation (120 rpm) at 28 °C for 96 h. Next, we aseptically transferred mycelia into new flasks containing 100 mL SDB media with 70 µg/mL of SRT hydrochloride (Cayman Chemical Co., Ann Arbor, MI, USA), corresponding to 70% of the minimal inhibitory concentration (MIC) [ 15 ], and in the absence of drugs (control). After 3 or 12 h of incubation at 28 °C with agitation, the resultant mycelia were collected, quick-frozen, and stored at −80 °C until RNA isolation.…”

“…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 ]. This synergistic association could decrease drug dosages and emerging drug resistance rates [ 6 ].…”

Alternative Splicing in Trichophyton rubrum Occurs in Efflux Pump Transcripts in Response to Antifungal Drugs

“…Other studies have highlighted the biofilm-associated antifungal resistance, as shown in M. canis , T. mentagrophytes [ 12 ], T. rubrum [ 34 ], and C. auris [ 26 ]. The mechanisms associated with antifungal resistance are the physical barrier conferred by the glucan matrix as well as cell signaling, which enhances regulatory mechanisms in this population [ 13 ].…”