Abstract
Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Infection of the gastrointestinal tract with this Gram-positive, obligate anaerobe can lead to potentially life-threatening conditions in the antibiotic-treated populace. New therapeutics are urgently needed to treat this infection and prevent its recurrence. Here, we screened two libraries from the National Cancer Institute, namely, the natural product set III library (117 compounds) and the approved oncology drugs set V library (114 compounds), against C. difficile. In the two libraries screened, 17 compounds from the natural product set III library and 7 compounds from the approved oncology drugs set V library were found to exhibit anticlostridial activity. The most potent FDA-approved drugs (mitomycin C and mithramycin A) and a promising natural product (aureomycin) were further screened against 20 clinical isolates of C. difficile. The anticancer drugs, mitomycin C (MIC50 = 0.25 μg/ml) and mithramycin A (MIC50 = 0.015 μg/ml), and the naturally derived tetracycline derivative, aureomycin (MIC50 = 0.06 μg/ml), exhibited potent activity against C. difficile strains. Mithramycin A and aureomycin were further found to inhibit toxin production by this pathogen. Given their efficacy, these compounds can provide a quick supplement to current treatment to address the unmet needs in treating C. difficile infection and preventing its recurrence.
Highlights
Clostridioides difficile is the leading cause of health care-associated diarrhea and mortality in the United States[1,2,3,4]
The current clinical practice guidelines for C. difficile infection (CDI) include the use of oral vancomycin and fidaxomicin as first-line agents for both nonsevere and severe episodes of infection[26]
The disadvantages associated with fidaxomicin include its prohibitive cost, lack of efficacy in patients infected with the NAP1/PCR ribotype 027 strains, and observed resistance in clinical settings[28,29]
Summary
Clostridioides difficile is the leading cause of health care-associated diarrhea and mortality in the United States[1,2,3,4]. In the absence of these gut microflora, following oral ingestion, the dormant C. difficile spores germinate, colonize the vacant nutrient niche in the gut, and release the enterotoxin TcdA and the cytotoxin TcdB9,10. These toxins A and B constitute the major virulence factors of the pathogen that damage the colonic epithelium triggering inflammatory responses that cause the range of symptoms associated with CDI10,11. The limitations in the current treatment options for CDI create an unmet medical need for novel antibacterial agents that can target the pathogen and prevent the recurrence of infection.
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