Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity
The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drug...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/96735 https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 |
| _version_ | 1811084678363348992 |
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| author | Carney, Daniel W. Schmitz, Karl R. Truong, Jonathan V. Sello, Jason K. Sauer, Robert T |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Carney, Daniel W. Schmitz, Karl R. Truong, Jonathan V. Sello, Jason K. Sauer, Robert T |
| author_sort | Carney, Daniel W. |
| collection | MIT |
| description | The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP–ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products. |
| first_indexed | 2024-09-23T12:55:19Z |
| format | Article |
| id | mit-1721.1/96735 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:55:19Z |
| publishDate | 2015 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/967352022-09-28T10:54:29Z Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity Carney, Daniel W. Schmitz, Karl R. Truong, Jonathan V. Sello, Jason K. Sauer, Robert T Massachusetts Institute of Technology. Department of Biology Schmitz, Karl R. Sauer, Robert T. The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP–ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products. National Science Foundation (U.S.) (NSF CAREER Award) Brown University National Institutes of Health (U.S.) (NIH Grant GM-101988) 2015-04-23T15:16:52Z 2015-04-23T15:16:52Z 2014-02 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/96735 Carney, Daniel W., Karl R. Schmitz, Jonathan V. Truong, Robert T. Sauer, and Jason K. Sello. “Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity.” Journal of the American Chemical Society 136, no. 5 (February 5, 2014): 1922–1929. © 2014 American Chemical Society. https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 en_US http://dx.doi.org/10.1021/ja410385c Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) American Chemical Society |
| spellingShingle | Carney, Daniel W. Schmitz, Karl R. Truong, Jonathan V. Sello, Jason K. Sauer, Robert T Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title | Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title_full | Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title_fullStr | Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title_full_unstemmed | Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title_short | Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity |
| title_sort | restriction of the conformational dynamics of the cyclic acyldepsipeptide antibiotics improves their antibacterial activity |
| url | http://hdl.handle.net/1721.1/96735 https://orcid.org/0000-0002-9309-8662 https://orcid.org/0000-0002-1719-5399 |
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