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dc.contributor.authorCarney, Daniel W.
dc.contributor.authorSchmitz, Karl R.
dc.contributor.authorTruong, Jonathan V.
dc.contributor.authorSauer, Robert T.
dc.contributor.authorSello, Jason K.
dc.date.accessioned2015-04-23T15:16:52Z
dc.date.available2015-04-23T15:16:52Z
dc.date.issued2014-02
dc.identifier.issn0002-7863
dc.identifier.issn1520-5126
dc.identifier.urihttp://hdl.handle.net/1721.1/96735
dc.description.abstractThe 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.en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (NSF CAREER Award)en_US
dc.description.sponsorshipBrown Universityen_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH Grant GM-101988)en_US
dc.language.isoen_US
dc.publisherAmerican Chemical Society (ACS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1021/ja410385cen_US
dc.rightsArticle 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.en_US
dc.sourceAmerican Chemical Societyen_US
dc.titleRestriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activityen_US
dc.typeArticleen_US
dc.identifier.citationCarney, 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.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorSchmitz, Karl R.en_US
dc.contributor.mitauthorSauer, Robert T.en_US
dc.relation.journalJournal of the American Chemical Societyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsCarney, Daniel W.; Schmitz, Karl R.; Truong, Jonathan V.; Sauer, Robert T.; Sello, Jason K.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9309-8662
dc.identifier.orcidhttps://orcid.org/0000-0002-1719-5399
mit.licensePUBLISHER_POLICYen_US


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