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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Peptoclostridium Difficile (strain 630) (clostridium Difficile)

SUBMITTER: Daniela Zuehlke

LAB HEAD: Susanne Sievers

PROVIDER: PXD027366 | Pride | 2021-12-21

REPOSITORIES: Pride

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			Action	DRS
	210407_HF2_DZ_MB_D1_1-5.raw	Raw
	210407_HF2_DZ_MB_D1_2-6.raw	Raw
	210407_HF2_DZ_MB_D1_3-7.raw	Raw
	210407_HF2_DZ_MB_D1_4-8.raw	Raw
	210407_HF2_DZ_MB_Rif1_1-5.raw	Raw

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Project description:Bacteroides fragilis is an anaerobic commensal in the human gut which can act as opportunistic pathogen when leaving its intestinal niche to reach other body sites. Bacteroides infections have a high lethality and must be treated by antimicrobial chemotherapy. Metronidazole is one of the most frequently administered antimicrobials in the treatment of Bacteroides infections and is highly reliable. However, metronidazole resistance does occur, favoring fatal disease outcomes. Most of the resistant isolates harbor a nim gene (12 are currently known, i.e. nimA to nimL), a transferable resistance determinant for metronidazole. Previous research suggested that Nim proteins might affect the cellular physiology by changing the activity of key enzymes like pyruvate:ferredoxin oxidoreductase (PFOR). In this study we wanted to assess the impact of the nimA gene on protein expression in a standard B. fragilis isolate, 638R, and compared overall protein expression in 638R with and without a nim gene and with the nimA gene in a proteomic study. Further, high-level metronidazole resistance was induced in both strains and the protein expression profiles of resulting resistant daughter strains were also compared with their respective parent strains. We found that comparably few proteins displayed altered expression in 638R with the nimA gene, but flavodiiron protein FprA was repeatedly found upregulated. FprA is often found in anaerobes and reduces molecular oxygen to water and/or nitric oxide to nitrous oxide. After induction of metronidazole resistance, a far higher number of proteins were found to be differentially expressed in 638R without nimA than in 638R with nimA. In the former, factors for the import of hemin were strongly downregulated, indicating impaired iron import, whereas in the latter the observed changes were not only less numerous but also less specific. Based on the results of this study we present a novel hypothetic model of metronidazole resistance and Nim function.

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

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