Abstract
The anaerobic, gastrointestinal pathogen Clostridioides difficile can cause severe forms of enterocolitis which is mainly mediated by the toxins it produces. The RNA polymerase inhibitor Fidaxomicin is the current gold standard for the therapy of C. difficile infections due to several beneficial features including its ability to suppress toxin synthesis in C. difficile. In contrast to the Rifamycins, Fidaxomicin binds to the RNA polymerase switch region, which is also the binding site for Myxopyronin B. Here, serial broth dilution assays were performed to test the susceptibility of C. difficile and other anaerobes to Myxopyronin B, proving that the natural product is considerably active against C. difficile and that there is no cross-resistance between Fidaxomicin and Myxopyronin B in a Fidaxomicin-resistant C. difficile strain. Moreover, mass spectrometry analysis indicated that Myxopyronin B is able to suppress early phase toxin synthesis in C. difficile to the same degree as Fidaxomicin. Conclusively, Myxopyronin B is proposed as a new lead structure for the design of novel antibiotics for the therapy of C. difficile infections.
Highlights
The anaerobic, spore-forming pathogen Clostridioides difficile infects the intestine of higher mammals, especially of humans and pigs, after colonization resistance that is generally provided by the microbiota is disrupted, e.g. after antibiotic therapy [1,2,3,4]
This study confirmed the antimicrobial activity of Myxopyronin B against a Fidaxomicin-resistant C. difficile strain, mapped the proteome stress signature that is caused by Myxopyronin B in C. difficile compared to other RNA polymerase inhibitors, and investigated the effect of Myxopyronin B on toxin synthesis
No cross‐resistance with Myxopyronin B in a Fidaxomicin‐resistant C. difficile isolate As a starting point, the sensitivity of five C. difficile strains to the reference antibiotic Rifaximin and the natural product Myxopyronin B was determined in serial broth dilution assays
Summary
The anaerobic, spore-forming pathogen Clostridioides difficile infects the intestine of higher mammals, especially of humans and pigs, after colonization resistance that is generally provided by the microbiota is disrupted, e.g. after antibiotic therapy [1,2,3,4]. In contrast to the Rifamycins, Fidaxomicin and other RNA polymerase inhibitors, such as the myxobacterial natural products Myxopyronins, Corallopyronin and Ripostatin, target the RNA polymerase switch region, which is required for the opening of the RNA:DNA clamp [16, 17]. Thereby, they interfere with the transcriptional process at an earlier stage than Rifamycins and do not show cross-resistance with Rifamycin and its derivatives [16,17,18,19]. This study confirmed the antimicrobial activity of Myxopyronin B against a Fidaxomicin-resistant C. difficile strain, mapped the proteome stress signature that is caused by Myxopyronin B in C. difficile compared to other RNA polymerase inhibitors, and investigated the effect of Myxopyronin B on toxin synthesis
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