Novel erythromycin resistance mechanism mediated by mrma methyltransferase in c. difficile

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F25%3A00642331" target="_blank" >RIV/61388971:_____/25:00642331 - isvavai.cz</a>

Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

Novel erythromycin resistance mechanism mediated by mrma methyltransferase in c. difficile

Original language description

Clostridioides difficile is a leading cause of hospital hospital-acquired diarrhea. However, the rise of antimicrobial resistance in epidemic C. difficile lineages compromises treatment efficacy and increases the risk of spreading resistance to other pathogens 1nWe have identified a novel macrolide resistance gene, mrmA (macrolide resistance methyltransferase A), by comparative genomic analysis of erythromycin erythromycin-susceptible and resistant C. difficile strains 2 . The encoded MrmA, a putative SAM SAM-radical 23S rRNA methyltransferase, shares homology with RlmN and Cfr. RlmN methylates the C2 atom at nucleotide A2503, which controls translational accuracy, whereas Cfr methylates the C8 atom at the same nucleotide, resulting in resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A, but not to erythromycin 3 . However, heterologous expression of mrmA in E. coli resulted only in specific resistance to erythromycin and streptogramin B. We hypothesize that MrmA (Figure 1), similar to RlmN or Cfr, possesses methyltransferase activity but targets a distinct adenine position, disrupting macrolide and streptogramin B binding. Direct 23S rRNA nanopore sequencing and primer extension assays have indeed revealed altered methylation patterns at the 23S rRNA nucleotidenA2058 in strains producing MrmA. This nucleotide is typically dimethylated at its N6 atom by Erm Erm-family methyltransferases, conferring broad resistance to macrolides, lincosamides, and streptogramin B antibiotics. Structural basis of MrmA MrmA-mediated ribosome modification was determine by CryoCryo-EM studies and reveal new methylation on C2 of A2058. This research uncovers a unique resistance mechanism mediated by RlmN RlmN-family enzymes in C. difficile , providing new insights into their substrate adaptability and the evolution of antibiotic resistance.

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

10606 - Microbiology

Project

<a href="/en/project/LX22NPO5103" target="_blank" >LX22NPO5103: National Institute of Virology and Bacteriology</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů