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

Autor: Crowe-McAuliffe C; Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany., Murina V; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187, Umeå, Sweden.; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87, Umeå, Sweden.; Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden., Turnbull KJ; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187, Umeå, Sweden.; Department of Clinical Microbiology, Rigshospitalet, 2200, Copenhagen, Denmark., Huch S; SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, 171 65, Solna, Sweden., Kasari M; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187, Umeå, Sweden.; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87, Umeå, Sweden.; University of Tartu, Institute of Technology, 50411, Tartu, Estonia., Takada H; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187, Umeå, Sweden.; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87, Umeå, Sweden.; Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo, Motoyama, Kita-ku, Kyoto, 603-8555, Japan., Nersisyan L; SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, 171 65, Solna, Sweden., Sundsfjord A; Department of Microbiology and Infection Control, Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway, Tromsø, Norway.; Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway., Hegstad K; Department of Microbiology and Infection Control, Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway, Tromsø, Norway.; Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037, Tromsø, Norway., Atkinson GC; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87, Umeå, Sweden.; Department of Experimental Medical Science, Lund University, 221 00, Lund, Sweden., Pelechano V; SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, 171 65, Solna, Sweden., Wilson DN; Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany. Daniel.Wilson@chemie.uni-hamburg.de., Hauryliuk V; Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187, Umeå, Sweden. vasili.hauryliuk@med.lu.se.; Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87, Umeå, Sweden. vasili.hauryliuk@med.lu.se.; Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden. vasili.hauryliuk@med.lu.se.; University of Tartu, Institute of Technology, 50411, Tartu, Estonia. vasili.hauryliuk@med.lu.se.; Department of Experimental Medical Science, Lund University, 221 00, Lund, Sweden. vasili.hauryliuk@med.lu.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 06; Vol. 13 (1), pp. 1860. Date of Electronic Publication: 2022 Apr 06.
DOI: 10.1038/s41467-022-29274-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: