Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate

Abstract

Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs againstLeishmaniashare this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets inLeishmaniawere poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline onLeishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on the bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress inL. infantumpromastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as a shortage of intracellular amino acids used as metabolic fuel byLeishmania. Sertraline killedLeishmaniathrough a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.

Synergistic Therapies as a Promising Option for the Treatment of Antibiotic-Resistant Helicobacter pylori

“…Sertraline is an antidepressant drug that is widely applied in the treatment of anxiety and obsessive-compulsive disorders ( Table 1 ) [ 40 , 41 , 42 , 43 , 44 , 45 ]. The mechanism of action of this compound is based on the inhibition of serotonin reuptake.…”

Potential of Bacterial Cellulose Chemisorbed with Anti-Metabolites, 3-Bromopyruvate or Sertraline, to Fight against Helicobacter pylori Lawn Biofilm

“…For both strains, a growth inhibition effect was significantly higher when an amount of grown colonies was read after three days of incubation than after a one week of culture (the post-treatment period). The reason of this phenomenon is unknown, but it seems that this mechanism was associated with an ability of both 3-BP and SER to reduce metabolism and intracellular ATP level [ 19 , 20 , 21 ]. This difference was not seen in bacteria treated with BIS or AMX, although there are studies showing an ability of BIS to disrupt H. pylori metabolism [ 53 , 54 , 55 ].…”

“…There are two promising compounds, namely 3-bromopyruvate (3-BP) and sertraline (SER), for which an antimicrobial activity against planktonic and biofilm forms of different pathogens was demonstrated [ 17 , 18 , 19 , 20 , 21 ]. Both of them affect a number of targets in microbial cells, including protein synthesis, metabolic pathways, and production of intracellular ATP.…”

In Vitro Activity of Sertraline, an Antidepressant, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains

“…The high bactericidal activity of SER against H. pylori may be associated with the presence of different targets for this compound and limited possibilities for developing resistance. In other pathogenic organisms, the ability of SER to damage the cell membrane [24], inhibit protein translation [17], reduce the amount of cytoplasmic ATP [26,27,29], lower intracellular pH [36], and interfere with metabolism (including tricarboxylic acid cycle) has been observed [27,29]. The effect of SER on H. pylori is not known, but these reports may be the starting point in future studies determining the molecular changes in the SER-treated cells of this microorganism.…”