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Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes

TO. Koller, KJ. Turnbull, K. Vaitkevicius, C. Crowe-McAuliffe, M. Roghanian, O. Bulvas, JA. Nakamoto, T. Kurata, C. Julius, GC. Atkinson, J. Johansson, V. Hauryliuk, DN. Wilson

. 2022 ; 50 (19) : 11285-11300. [pub] 2022Oct28

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22032964

HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.

Citace poskytuje Crossref.org

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$a HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.
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$a Turnbull, Kathryn J $u Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187 Umeå, Sweden $u Department of Clinical Microbiology, Rigshospitalet, 2200 Copenhagen, Denmark
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$a Crowe-McAuliffe, Caillan $u Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
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$a Roghanian, Mohammad $u Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90187 Umeå, Sweden $u Department of Clinical Microbiology, Rigshospitalet, 2200 Copenhagen, Denmark $u Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden
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$a Bulvas, Ondřej $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czech Republic $u Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technicka 5, 166 28 Prague 6, Czech Republic $7 xx0323147
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$a Nakamoto, Jose A $u Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden
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$a Wilson, Daniel N $u Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany $1 https://orcid.org/0000000338163828
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