Synergistic effect of sertraline and disulfiram against multidrug resistant bacteria as a new alternative to drug repositioning

Abstract

The repositioning of approved drugs is atopic of interest for the academy and the pharmaceutical industry. The synergistic combination of these drugs can be successful in the treatment of infections caused by resistant bacteria. This study aimed to assess the in vitro synergistic antibacterial activity of sertraline and disulfiram and their interaction with ciprofloxacin and sulfamethoxazole/trimethoprim. We determined the minimum inhibitory concentration, the minimum bactericidal concentration and the fractional inhibitory concentration index. Eighteen bacterial strains were used, being nine American Type Culture Collection reference strains and nine multidrug resistant clinical isolates. Synergy was detected between sertraline and disulfiram against a strain of Staphylococcus aureusATCC 25923 and a clinical isolate of S. aureus. When associated to sulfamethoxazole/trimethoprim and ciprofloxacin, sertraline and disulfiram showed eight synergistic events, which occurred against three different standard strains and two multidrug resistant clinical isolates. When the minimum bactericidal concentration was determined, the bactericidal activity of sertraline was enhanced with disulfiram. Our results suggest that these drugs, widely used to treat depression and chronic alcoholism, have antibacterial potential individually, in association, and combined with antimicrobials, what makes their repositioning a promising therapeutic alternative for the effective treatment of infections caused by multidrug resistant bacteria.

Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning

“…Disulfiram was metabolized by bacterial cells to diethyldithiocarbamate (DDTC), which has antibacterial properties. Additionally, disulfiram has a proteolytic effect due to its ability to chelate ions ( Serafin et al, 2020 ). Clinical trials also included combination therapy of fluconazole and sertraline in the treatment of early disseminated cryptococcal infection (NCT03002012).…”

Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre‐Clinical to Clinical Findings

“…Despite having some limitations, the reuse of clinical trials represent a good strategy, because it facilitates the reuse of drugs already approved, thus reducing the time and bureaucracy to reach the market [63] . Drug repurposing helps to develop new therapies with drugs that are already used clinically and whose tests with patients are already known [64] …”

Anti-infective properties of proton pump inhibitors: perspectives

“…Studies reporting the importance of drug repositioning for the treatment of infectious diseases are available, and among them we cite several classes, such as antidepressants (Bottega et al 2020;da Rosa et al , 2021Foletto et al 2020Foletto et al , 2021Machado et al 2020;Serafin et al 2020), antihypertensive (Hu et al 2018), antihistamines (Bruer et al 2019;El-Nakeeb et al 2011), anti-inflammatory (Chan et al 2017), alcohol-aversive agentes (Serafin et al 2020), benzodiazepines (da Rosa et al 2021, and statins (Rampelotto et al 2018). In this commentary, the class of proton pump inhibitors (PPIs) is emphasized.…”