Myxopyronin B inhibits growth of a Fidaxomicin-resistant Clostridioides difficile isolate and interferes with toxin synthesis

Fidaxomicin is considered the current gold standard antibiotic for treating Clostridioides difficile infections and kills bacterial cells by inhibition of the RNA polymerase through binding to its switch region. Although binding sites do not overlap, also Myxopyronin B inhibits the RNA polymerase by binding its switch region. The here presented data prove that there is no cross-resistance between Fidaxomicin and Myxopyronin B in a Fidaxomicin-resistant C. difficile strain. Moreover, comparative LC-MS/MS analyses of Fidaxomicin, Myxopyronin B and Rifaximin stress in C. difficile strain 630 revealed 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 lead structure for the design of novel antibiotics for the therapy of C. difficile infections.