The Antidepressant Sertraline Affects Cell Signaling and Metabolism in Trichophyton rubrum

Abstract

The dermatophyte Trichophyton rubrum is responsible for most human cutaneous infections. Its treatment is complex, mainly because there are only a few structural classes of fungal inhibitors. Therefore, new strategies addressing these problems are essential. The development of new drugs is time-consuming and expensive. The repositioning of drugs already used in medical practice has emerged as an alternative to discovering new drugs. The antidepressant sertraline (SRT) kills several important fungal pathogens. Accordingly, we investigated the inhibitory mechanism of SRT in T. rubrum to broaden the knowledge of its impact on eukaryotic microorganisms and to assess its potential for future use in dermatophytosis treatments. We performed next-generation sequencing (RNA-seq) to identify the genes responding to SRT at the transcript level. We identified that a major effect of SRT was to alter expression for genes involved in maintaining fungal cell wall and plasma membrane stability, including ergosterol biosynthetic genes. SRT also altered the expression of genes encoding enzymes related to fungal energy metabolism, cellular detoxification, and defense against oxidative stress. Our findings provide insights into a specific molecular network interaction that maintains metabolic stability and is perturbed by SRT, showing potential targets for its strategic use in dermatophytosis.

An efficient gene targeting system using Δku80and functional analysis of Cyp51A inTrichophyton rubrum

“…In this study, we generated a ku80-deficient strain of this fungus and demonstrated that this strain can be applied in efficient HR methods, similar to a system established in a zoophilic dermatophyte, T. mentagrophytes (formerly Arthroderma vanbreuseghemii) (35). The method established in this study might serve as a fundamental technique to promote research that will advance the findings of previous comprehensive analyses and immunological analyses observed on the host side (17,(29)(30)(31)(32)(33)(34).…”

“…The nature of this fungus is of great interest from not only a medical but also biological point of view. In recent years, transcriptomic, proteomic, and immunological studies of this fungus have been conducted extensively (17,(29)(30)(31)(32)(33)(34).…”

The Transcription Factor StuA Regulates the Glyoxylate Cycle in the Dermatophyte Trichophyton rubrum under Carbon Starvation

“…Given its absence in humans, this pathway is an attractive and promising target for antifungal development, primarily because of its exclusive non-human enzymes, isocitrate lyase, and malate synthase [ 1 ]. These enzymes become active in the dermatophyte T. rubrum when grown on keratin or when exposed to cytotoxic drugs in an infection-like scenario involving human keratinocytes [ 6 , 34 , 35 , 36 , 37 , 38 ]. For the first time, we present evidence of the transcriptional modulation of essential enzyme-coding genes within the glyoxylate cycle by StuA.…”

Atividade sinérgica do antidepressivo sertralina associada a caspofungina contra >i<Trichophyton rubrum>/i< e avaliação dos mecanismos de resposta adaptativa

“…Nesse fungo, SRT afetou a sinalização celular e o metabolismo. Além disso, identificamos que SRT pode alterar a expressão de genes envolvidos na manutenção da parede celular fúngica e estabilidade da membrana plasmática (Galvão-Rocha et al, 2023).…”

“…Em T. rubrum, os mecanismos moleculares relacionados com a resposta ao estresse, a tolerância ou resistência, são pouco conhecidos (Martinez- Rossi et al, 2018). Traçar o perfil de expressão de genes, fornece conhecimento para o desenvolvimento de novos fármacos e auxilia na compreensão dos processos envolvidos na resposta a um medicamento (Galvão-Rocha et al, 2023). Encontrar novos compostos com atividade antifúngica e novos alvos moleculares torna-se necessário e, neste sentido o reposicionamento de fármacos e combinações sinérgicas com antifúngicos clássicos revela-se como uma estratégia promissora Andriani et al, 2023).…”