Regulation of the macrolide resistance ABC-F translation factor MsrD
Abstract Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39553-8 |
| _version_ | 1797789700658823168 |
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| author | Corentin R. Fostier Farès Ousalem Elodie C. Leroy Saravuth Ngo Heddy Soufari C. Axel Innis Yaser Hashem Grégory Boël |
| author_facet | Corentin R. Fostier Farès Ousalem Elodie C. Leroy Saravuth Ngo Heddy Soufari C. Axel Innis Yaser Hashem Grégory Boël |
| author_sort | Corentin R. Fostier |
| collection | DOAJ |
| description | Abstract Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex. |
| first_indexed | 2024-03-13T01:54:24Z |
| format | Article |
| id | doaj.art-5e6afefbedb54340b1b468d142e39512 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T01:54:24Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5e6afefbedb54340b1b468d142e395122023-07-02T11:20:26ZengNature PortfolioNature Communications2041-17232023-07-0114111510.1038/s41467-023-39553-8Regulation of the macrolide resistance ABC-F translation factor MsrDCorentin R. Fostier0Farès Ousalem1Elodie C. Leroy2Saravuth Ngo3Heddy Soufari4C. Axel Innis5Yaser Hashem6Grégory Boël7Expression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-ChimiqueExpression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-ChimiqueARNA Laboratory, UMR 5320, U1212, Institut Européen de Chimie et Biologie, Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleExpression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-ChimiqueARNA Laboratory, UMR 5320, U1212, Institut Européen de Chimie et Biologie, Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleARNA Laboratory, UMR 5320, U1212, Institut Européen de Chimie et Biologie, Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleARNA Laboratory, UMR 5320, U1212, Institut Européen de Chimie et Biologie, Univ. Bordeaux, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleExpression Génétique Microbienne, CNRS, Université Paris Cité, Institut de Biologie Physico-ChimiqueAbstract Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex.https://doi.org/10.1038/s41467-023-39553-8 |
| spellingShingle | Corentin R. Fostier Farès Ousalem Elodie C. Leroy Saravuth Ngo Heddy Soufari C. Axel Innis Yaser Hashem Grégory Boël Regulation of the macrolide resistance ABC-F translation factor MsrD Nature Communications |
| title | Regulation of the macrolide resistance ABC-F translation factor MsrD |
| title_full | Regulation of the macrolide resistance ABC-F translation factor MsrD |
| title_fullStr | Regulation of the macrolide resistance ABC-F translation factor MsrD |
| title_full_unstemmed | Regulation of the macrolide resistance ABC-F translation factor MsrD |
| title_short | Regulation of the macrolide resistance ABC-F translation factor MsrD |
| title_sort | regulation of the macrolide resistance abc f translation factor msrd |
| url | https://doi.org/10.1038/s41467-023-39553-8 |
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