Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

Caillan Crowe-McAuliffe, Victoriia Murina, Kathryn Jane Turnbull, Susanne Huch, Marje Kasari, Hiraku Takada, Lilit Nersisyan, Arnfinn Sundsfjord, Kristin Hegstad, Gemma C. Atkinson, Vicent Pelechano, Daniel N. Wilson () and Vasili Hauryliuk ()
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Caillan Crowe-McAuliffe: Institute for Biochemistry and Molecular Biology, University of Hamburg
Victoriia Murina: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
Kathryn Jane Turnbull: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
Susanne Huch: SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet
Marje Kasari: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
Hiraku Takada: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University
Lilit Nersisyan: SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet
Arnfinn Sundsfjord: Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway
Kristin Hegstad: Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway
Gemma C. Atkinson: Umeå Centre for Microbial Research (UCMR), Umeå University
Vicent Pelechano: SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet
Daniel N. Wilson: Institute for Biochemistry and Molecular Biology, University of Hamburg
Vasili Hauryliuk: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

Date: 2022
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DOI: 10.1038/s41467-022-29274-9

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