» Articles » PMID: 25897961

Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus Aureus

Overview
Journal PLoS One
Date 2015 Apr 22
PMID 25897961
Citations 76
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Gold complex compounds that inhibit drug-resistant by targeting thioredoxin reductase.

Tharmalingam N, Xu S, Felix L, Roy B, Xian M, Mylonakis E Front Antibiot. 2025; 2():1179354.

PMID: 39816643 PMC: 11732138. DOI: 10.3389/frabi.2023.1179354.


Drug Repurposing: Research Progress of Niclosamide and Its Derivatives on Antibacterial Activity.

Liu Z, Liang X, Zhang Y, Deng W, Wang Y, Lu Z Infect Drug Resist. 2024; 17:4539-4556.

PMID: 39464831 PMC: 11505561. DOI: 10.2147/IDR.S490998.


A high-throughput assay identifies molecules with antimicrobial activity against persister cells.

Petersen M, Hansen L, Mitkin A, Kelly N, Wood T, Jorgensen N J Med Microbiol. 2024; 73(7).

PMID: 38995832 PMC: 11316564. DOI: 10.1099/jmm.0.001856.


Predicting lung exposure of intramuscular niclosamide as an antiviral agent: Power-law based pharmacokinetic modeling.

Kim T, Jung W, Cho S, Kim G, Yun H, Chae J Clin Transl Sci. 2024; 17(5):e13833.

PMID: 38797873 PMC: 11128490. DOI: 10.1111/cts.13833.


Synergistic antibacterial effects of closantel and its enantiomers in combination with colistin against multidrug resistant gram-negative bacteria.

Ding T, Guo Z, Fang L, Guo W, Yang Y, Li Y Front Microbiol. 2024; 15:1374910.

PMID: 38765678 PMC: 11100319. DOI: 10.3389/fmicb.2024.1374910.


References
1.
Haste N, Hughes C, Tran D, Fenical W, Jensen P, Nizet V . Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011; 55(7):3305-12. PMC: 3122406. DOI: 10.1128/AAC.01211-10. View

2.
Rahme L, Stevens E, Wolfort S, Shao J, Tompkins R, Ausubel F . Common virulence factors for bacterial pathogenicity in plants and animals. Science. 1995; 268(5219):1899-902. DOI: 10.1126/science.7604262. View

3.
Jayamani E, Rajamuthiah R, Larkins-Ford J, Fuchs B, Conery A, Vilcinskas A . Insect-derived cecropins display activity against Acinetobacter baumannii in a whole-animal high-throughput Caenorhabditis elegans model. Antimicrob Agents Chemother. 2015; 59(3):1728-37. PMC: 4325797. DOI: 10.1128/AAC.04198-14. View

4.
Rice L . Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol. 2010; 31 Suppl 1:S7-10. DOI: 10.1086/655995. View

5.
Kratky M, Bosze S, Baranyai Z, Szabo I, Stolarikova J, Paraskevopoulos G . Synthesis and in vitro biological evaluation of 2-(phenylcarbamoyl)phenyl 4-substituted benzoates. Bioorg Med Chem. 2015; 23(4):868-75. DOI: 10.1016/j.bmc.2014.12.019. View