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Deworming drugs show promise against hypervirulent C. difficile
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Repurposed anti-worm drugs known as salicylanilides may be effective at combating hypervirulent strains of Clostridium difficile infection, according to a recent study conducted by The Scripps Research Institute.
“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,” Kim D. Janda, PhD, the Ely R. Callaway Jr. Professor of Chemistry, director of the Worm Institute for Research and Medicine and member of the Skaggs Institute for Chemical Biology at The Scripps Research Institute, said in a press release.
Escalating rates of C. difficile infections (CDI) pose a major health threat and are associated with high rates of mortality. Current treatment options, including metronidazole, vancomycin and fidaxomicin, have proven insufficient for combating recurring hypervirulent strains of C. difficile, the researchers said.
Recently, drugs that are active against the C. difficile membrane have appeared promising in targeting stationary-phase C. difficile cells and demonstrate low propensity for resistance. Salicylanilides are membrane-active agents that have been reported to exhibit antimicrobial properties as well as low oral bioavailability. Therefore, Janda and TSRI postdoctoral fellow Major Gooyit, PhD, investigated the potential of salicylanilides in fighting CDI.
They tested the effectiveness of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide and oxyclozanide) at targeting C. difficile bacteria. They used broth microdilution techniques to determine the minimum inhibitory concentration (MIC) values of the anthelmintics against 16 C. difficile isolates.
The investigators determined that the anthelmintics broadly inhibited the growth of a range of C. difficile strains, including the hypervirulent BI/NAP1/027 strain, with MICs as low as 0.06 to 0.13 μg/mL for rafoxanide. Furthermore, closantel and rafoxanide were found to be effective against stationary-phase C. difficile cells, whereas metronidazole and vancomycin have little effect on these targets.
To assess the potential for the development of resistance in vitro, Janda and Gooyit conducted serial passaging of CD4118 at sub-inhibitory concentrations of the salicylanilides and reported that “changes in MICs after serial passages were minimal … suggesting that emergence of resistance is likely to be low.”
Study researchers Kim D. Janda, PhD (left), and Major Gooyit, PhD, of The Scripps Research Institute.
Source: TSRI
The researchers noted that salicylanilides have additional desirable properties as anti-C. difficile agents because, when taken orally, they are not well-absorbed into the bloodstream. Therefore, their effects are restricted to the gut and side effects elsewhere are minimized.
“Killing of hypervirulent stationary-phase C. difficile could likely suppress toxin production and sporulation, which in principle may lead to an improved sustained response and reduced recurrence rate,” the researchers concluded. “Our results exemplify notable attributes of membrane-active salicylanilide anthelmintics and demonstrate their potential for repurposing as anti-Clostridium difficile agents.” – by Sarah Kennedy
Disclosure: The researchers report no relevant financial disclosures.
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