Drugs for deworming cattle also conquer virulent C. difficile, researchers discover

By John Murphy, MDLinx
Published September 16, 2016

Key Takeaways

Researchers serendipitously discovered that antiparasitics used to deworm cattle can also kill harmful, even fatal, strains of Clostridium difficile, according to a September 16, 2016 study published in Scientific Reports.

These antiparasitic agents belong to the class of salicylanilides, which are currently used to eradicate tapeworms, roundworms, and flukes in sheep, cows and goats. In this study, the researchers showed that salicylanilides are also bactericidal against a number of C. difficile strains, including hypervirulent, resistant strains.

“These salicylanilide compounds have all the right features, and they’ve long been used in animals, so I think they can be quickly repurposed against C. difficile infections in people,” said senior author Kim D. Janda, PhD, Professor of Chemistry and Director of the Worm Institute for Research & Medicine (WIRM) at The Scripps Research Institute (TSRI), in La Jolla, CA.

Interestingly, the researchers discovered the salicylanilides’ bactericidal effect by happenstance, even though they had been seeking an agent that would be effective against C. difficile. “We started looking at other compounds for their effects on C. difficile and happened to be using a salicylanilide called closantel as a control,” Dr. Janda explained.

When the researchers noticed the effectiveness of the ‘control,’ they started testing closantel and three other salicylanilides—rafoxanide, niclosamide, and oxyclozanide—against 16 cultured strains of C. difficile. (Closantel, rafoxanide, and oxyclozanide are FDA-approved for veterinary use only, while niclosamide is approved for treating tapeworm infections in humans.)

“We found that these salicylanilides inhibited the growth of a broad selection of strains, including the BI/NAP1/027 strain, with similar and sometimes greater in vitro activity than metronidazole’s and vancomycin’s,” said first author Major Gooyit, PhD, Research Associate in Dr. Janda’s lab.

BI/NAP1/027 is a hypervirulent, epidemic C. difficile strain that is highly resistant to antibiotics, and has been associated with numerous outbreaks in the U.S. and other countries. Metronidazole and vancomycin are the standard treatment options for moderate cases of C. difficile, but these agents are becoming increasingly ineffective against resistant strains.

The researchers performed additional in vitro experiments in which they observed that the two most active salicylanilides, closantel and rafoxanide, maintained their effectiveness against C. difficile cells in the quiescent, stationary-phase—the phase when C. difficile cells produce the most toxins and spores. Metronidazole and vancomycin, by comparison, were not effective against stationary-phase cells.

The researchers confirmed that the salicylanilides work differently than metronidazole and vancomycin against C. difficile. Although the exact mechanism is not yet known, the salicylanilides appear to attack and destabilize the pathogen’s cell membrane, resulting in cell death.

The salicylanilides also have poor oral bioavailability, the researchers noted. This is an advantage because it means the agents should conserve their concentrations in the gut, where the active drug must maintain a therapeutic level to neutralize C. difficile.

The researchers also tested hypervirulent C. difficile strains for potential resistance to the salicylanilides, and found that their likelihood of resistance is low.

Such findings support the idea of repurposing these deworming drugs to become anti-C. difficile agents, the researchers concluded. “We’re now testing these compounds in animal models of C. difficile infections,” Dr. Gooyit said. In fact, they are currently working on licensing the salicylanilides to a pharmaceutical company for further development as a C. difficile treatment, Dr. Janda noted.

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