OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo
Abstract Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes o...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2019-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-019-11756-y |
| _version_ | 1797840898067791872 |
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| author | Joshua L. C. Wong Maria Romano Louise E. Kerry Hok-Sau Kwong Wen-Wen Low Stephen J. Brett Abigail Clements Konstantinos Beis Gad Frankel |
| author_facet | Joshua L. C. Wong Maria Romano Louise E. Kerry Hok-Sau Kwong Wen-Wen Low Stephen J. Brett Abigail Clements Konstantinos Beis Gad Frankel |
| author_sort | Joshua L. C. Wong |
| collection | DOAJ |
| description | Abstract Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggests that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost. |
| first_indexed | 2024-04-09T16:22:14Z |
| format | Article |
| id | doaj.art-048fe9334b3d4543a8b1643b71a6d1c0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T16:22:14Z |
| publishDate | 2019-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-048fe9334b3d4543a8b1643b71a6d1c02023-04-23T11:21:24ZengNature PortfolioNature Communications2041-17232019-09-0110111010.1038/s41467-019-11756-yOmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivoJoshua L. C. Wong0Maria Romano1Louise E. Kerry2Hok-Sau Kwong3Wen-Wen Low4Stephen J. Brett5Abigail Clements6Konstantinos Beis7Gad Frankel8Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College LondonDepartment of Life Sciences, Imperial College LondonCentre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College LondonDepartment of Life Sciences, Imperial College LondonCentre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College LondonDepartment of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College LondonCentre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College LondonDepartment of Life Sciences, Imperial College LondonCentre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College LondonAbstract Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggests that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost.https://doi.org/10.1038/s41467-019-11756-y |
| spellingShingle | Joshua L. C. Wong Maria Romano Louise E. Kerry Hok-Sau Kwong Wen-Wen Low Stephen J. Brett Abigail Clements Konstantinos Beis Gad Frankel OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo Nature Communications |
| title | OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo |
| title_full | OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo |
| title_fullStr | OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo |
| title_full_unstemmed | OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo |
| title_short | OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo |
| title_sort | ompk36 mediated carbapenem resistance attenuates st258 klebsiella pneumoniae in vivo |
| url | https://doi.org/10.1038/s41467-019-11756-y |
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