Repurposing Disulfiram as an Antimicrobial Agent in Topical Infections

Abstract

Antimicrobial drugs applied topically offer several advantages. However, the widespread use of antibiotics has led to increasing antimicrobial resistance. One interesting approach in the drug discovery process is drug repurposing. Disulfiram, which was originally approved as an anti-alcoholism drug, offers an attractive alternative to treat topical multidrug resistance bacteria in skin human infections. This study aimed to evaluate the biopharmaceutical characteristics of the drug and the effects arising from its topical application in detail. Microdilution susceptibility testing showed antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. Dermal absorption revealed no permeation in pig skin. The quantification of the drug retained in pig skin demonstrated concentrations in the stratum corneum and epidermis, enough to treat skin infections. Moreover, in vitro cytotoxicity and micro-array analyses were performed to better understand the mechanism of action and revealed the importance of the drug as a metal ion chelator. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic to treat superficial human skin infections.

Repurposing Disulfiram as an Antifungal Agent: Development of a New Disulfiram Vaginal Mucoadhesive Gel

“…The key aspects of the disulfiram mode of action that could explain its antifungal activity can be understood by two effects. First, disulfiram is a chelator agent that can sequester copper and consequently alter various metabolic pathways in cells; and second, D has an affinity for the thiol groups of cysteine residues in several cellular targets [ 21 , 22 ]. D may be considered a potential agent for the treatment of candidiasis.…”

“…In other permeation studies involving human and pig skin, D showed a lack of permeability [ 21 , 22 ]. These differences are due to the nonkeratinization of the vaginal epithelium, and the increase in surface area provided by the transversal rugae of the mucosa would also increase drug absorption across this tissue [ 60 ].…”

“…The in vitro release of D from the mucoadhesive gels was studied using vertical Franz cells (Vidrafoc, Barcelona, Spain) with a 12 mL receptor compartment and an effective diffusion area of 1.54 cm 2 . A 15% w / w HPCD solution in PBS (pH 5.5) was used as the receptor medium (RM) at 37 °C with stirring at 500 rpm to maintain sink conditions throughout the experiment due to the poor water solubility of D (4.09 mg/L) [ 20 ] and according to previous studies reported [ 21 , 22 ]. A total of 0.0545 g/cm 2 gel was applied in the donor compartment, corresponding to 420 μg of D for the 0.5% formulation ( n = 5) and 840 μg of D for the 1% formulation ( n = 5).…”

“…In accordance with its physicochemical properties, a good permeation profile is expected. Different in vitro and in vivo studies have shown that D could be an active substance against scabies, lice, and bacteria [ 21 , 22 ]. Furthermore, the effectiveness of D against fungi and cancer was reported [ 23 , 24 ].…”

“…Furthermore, the effectiveness of D against fungi and cancer was reported [ 23 , 24 ]. Different mechanisms of action have been proposed to explain the antimicrobial activity of D: metal ion chelation, which affects cell homeostasis, and the presence of reactive thiol groups, which can impact the functions of proteins by forming incorrect disulfide bonds [ 22 ]. D was found to be potentially useful by inhibiting the function of glycoprotein P (P-gp) and has also been shown to act as a modulator of other multidrug transporters, such as MRP1 and MRP4 [ 25 ].…”