Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus

Abstract

Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

“…We observed that, in agreement with recent reports by Rajamuthiah et al (13), niclosamide showed strong antimicrobial activity against planktonic S. aureus with an IC 50 of 1.2 M. Furthermore, closantel, a homologue of niclosamide, also showed significant antimicrobial activity against planktonic S. aureus with an IC 50 below the lowest concentration tested (0.6 M), in agreement with the findings of Macielag et al (14).…”

Repurposing niclosamide as a versatile antimicrobial surface coating against device-associated, hospital-acquired bacterial infections

“…Niclosamide activity was recently examined against the prevalent ESKAPE pathogens ( Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa , and Enterobacter species). [21] This work showed that niclosamide exhibits potent activity against only the Gram-positive members of the ESKAPE pathogens. [21] Due to the prevalence of S. epidermidis in hospital-acquired infections, [1] we sought to examine whether niclosamide is capable of inhibiting S. epidermidis growth.…”

“…The drug was found to be bacteriostatic and displayed minimum inhibitory concentrations (MICs) far below that of vancomycin, which is commonly used in MRSA treatments. [21] The absence of any reported resistance to niclosamide, along with its potent efficacy against Gram-positive bacteria, makes it a promising alternative to conventional antibiotics. Although niclosamide has shown promising antimicrobial properties, its potential for use in localized infection treatments as part of a medical device coating has not yet been explored.…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Niclosamide displayed toxicity to mammalian cells even at low concentrations [14]. Human volunteers given an oral dose of 2 g niclosamide exhibited maximal serum concentration of 0.25-6 μg/ml and eliminated the drug within 2 days.…”

“…(5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydrobenzamide) is a teniacide which is especially effective against cestodes that infect humans and many animals [14]. Niclosamide displayed toxicity to mammalian cells even at low concentrations [14].…”