Abstract
Clostridium difficile infections (CDIs) are a growing health concern worldwide. The recalcitrance of C. difficile spores to currently available treatments and concomitant virulence of vegetative cells has made it imperative to develop newer modalities of treatment. Aryl-alkyl-lysines have been earlier reported to possess antimicrobial activity against pathogenic bacteria, fungi, and parasites. Their broad spectrum of activity is attributed to their ability to infiltrate microbial membranes. Herein, we report the activity of aryl-alkyl-lysines against C. difficile and associated pathogens. The most active compound NCK-10 displayed activity comparable to the clinically-used antibiotic vancomycin. Indeed, against certain C. difficile strains, NCK-10 was more active than vancomycin in vitro. Additionally, NCK-10 exhibited limited permeation across the intestinal tract as assessed via a Caco-2 bidirectional permeability assay. Overall, the findings suggest aryl-alkyl-lysines warrant further investigation as novel agents to treat CDI.
Highlights
Clostridium difficile infections (CDIs) are a growing health concern worldwide
Most CDIs can be treated with antibiotics such as metronidazole, vancomycin and fidaxomicin, the spread of hypervirulent strains such as PCR ribotype 027 poses a major challenge[4]
Compounding the challenge further is certain bacterial species that coexist with C. difficile in the intestinal tract, such as Enterococcus, have already developed resistance to vancomycin
Summary
Clostridium difficile infections (CDIs) are a growing health concern worldwide. The recalcitrance of C. difficile spores to currently available treatments and concomitant virulence of vegetative cells has made it imperative to develop newer modalities of treatment. Aryl-alkyl-lysines have been earlier reported to possess antimicrobial activity against pathogenic bacteria, fungi, and parasites. Compounding the challenge further is certain bacterial species that coexist with C. difficile in the intestinal tract, such as Enterococcus, have already developed resistance to vancomycin. Few synthetic mimics of AMPs have been explored for treatment of infections caused by C. difficile the bacterial membrane is considered to be an attractive target for novel antibacterial agents[20,21]. Aryl-alkyl-lysines were earlier reported as peptidomimetic membrane-active antibacterial agents[22]. They exhibited activity against both Gram-positive and Gram-negative bacteria in animal models of skin infection[23,24]. Caco-2 permeability assay was conducted with one of the most promising compounds to establish the utility of the compounds for treatment of C. difficile infection in colon
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