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Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria: VmlR2, Ard1 and CplR

Authors :
Nozomu Obana
Hiraku Takada
Caillan Crowe-McAuliffe
Mizuki Iwamoto
Artyom A Egorov
Kelvin J Y Wu
Shinobu Chiba
Victoriia Murina
Helge Paternoga
Ben I C Tresco
Nobuhiko Nomura
Andrew G Myers
Gemma C Atkinson
Daniel N Wilson
Vasili Hauryliuk
Source :
Nucleic Acids Research. 51:4536-4554
Publication Year :
2023
Publisher :
Oxford University Press (OUP), 2023.

Abstract

Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The single-particle cryo-EM structure of a VmlR2-ribosome complex allows us to rationalise the resistance spectrum of this ARE-ABCF that is equipped with an unusually long antibiotic resistance determinant (ARD) subdomain. We show that CplR contributes to intrinsic pleuromutilin, lincosamide and streptogramin A resistance in Clostridioides, and demonstrate that C. difficile CplR (CDIF630_02847) synergises with the transposon-encoded 23S ribosomal RNA methyltransferase Erm to grant high levels of antibiotic resistance to the C. difficile 630 clinical isolate. Finally, assisted by uORF4u, our novel tool for detection of upstream open reading frames, we dissect the translational attenuation mechanism that controls the induction of cplR expression upon an antibiotic challenge.

Details

ISSN :
13624962 and 03051048
Volume :
51
Database :
OpenAIRE
Journal :
Nucleic Acids Research
Accession number :
edsair.doi.dedup.....f0d26f7fbc7cdcb357bec011d2f729f9
Full Text :
https://doi.org/10.1093/nar/gkad193