A Novel Phosphodiesterase of the GdpP Family Modulates Cyclic di-AMP Levels in Response to Cell Membrane Stress in Daptomycin-Resistant Enterococci

Simple item page
dc.contributor.advisorShamoo, Yousifen_US
dc.contributor.advisorOlson, Johnen_US
dc.creatorWang, Xuen_US
dc.date.accessioned2017-08-01T17:20:53Zen_US
dc.date.available2017-11-01T05:01:06Zen_US
dc.date.created2017-05en_US
dc.date.issued2017-04-17en_US
dc.date.submittedMay 2017en_US
dc.date.updated2017-08-01T17:20:53Zen_US
dc.description.abstractAntimicrobial resistance is a serious and growing threat to public health. The Centers for Disease Control estimates that at least 2 million people contract serious infections each year resulting in at least 23,000 deaths each year in the United States alone. To develop more effective treatments, it is important to understand the fundamental biology underlying the mechanisms of antibiotic resistance. Substitutions in the LiaFSR membrane stress response pathway are frequently associated with emergence of antimicrobial peptide resistance in both Enterococcus faecalis and Enterococcus faecium. Cyclic di-AMP (c-di-AMP) is an important signal molecule that affects many aspects of bacterial physiology including stress response. We have previously identified a mutation in a gene (designated yybT) of E. faecalis that was associated with development of daptomycin resistance. The adaptive mutation produced a change at position 440 in the predicted protein (yybTI440S). Here, we show that intracellular cyclic di-AMP signaling is present in enterococci and, based upon in vitro physicochemical characterization, we show that E. faecalis yybT encodes a cyclic dinucleotide phosphodiesterase of the GdpP family that exhibits specific activity toward c-di-AMP by hydrolyzing it to 5’pApA. The E. faecalis GdpPI440S substitution reduces cyclic di-AMP phosphodiesterase activity more than 11-fold leading to further increases in cyclic di-AMP levels. Additionally, deletions of liaR (encoding the response regulator of the LiaFSR system) that lead to daptomycin hypersusceptibility in both E. faecalis and E. faecium also resulted in increased cyclic-di-AMP levels suggesting that changes in the LiaFSR stress response pathway are linked to broader physiological changes. Taken together, our data show that modulation of cyclic di-AMP pools is strongly associated with antibiotic-induced cell membrane stress response via changes in GdpP activity and signaling through the LiaFSR system.en_US
dc.embargo.terms2017-11-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationWang, Xu. "A Novel Phosphodiesterase of the GdpP Family Modulates Cyclic di-AMP Levels in Response to Cell Membrane Stress in Daptomycin-Resistant Enterococci." (2017) Diss., Rice University. <a href="https://hdl.handle.net/1911/96049">https://hdl.handle.net/1911/96049</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/96049en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinGdpPen_US
dc.subjectc-di-AMPen_US
dc.subjectenterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectEnterococcus faeciumen_US
dc.subjectLiaFSRen_US
dc.subjectmembrane stressen_US
dc.subjectcyclic dinucleotideen_US
dc.subjectdaptomycinen_US
dc.titleA Novel Phosphodiesterase of the GdpP Family Modulates Cyclic di-AMP Levels in Response to Cell Membrane Stress in Daptomycin-Resistant Enterococcien_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
WANG-DOCUMENT-2017.pdf
Size:
6.84 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 2 of 2
No Thumbnail Available
Name:
PROQUEST_LICENSE.txt
Size:
5.84 KB
Format:
Plain Text
Description:
Download
No Thumbnail Available
Name:
LICENSE.txt
Size:
2.6 KB
Format:
Plain Text
Description:
Download
Collections
Rice University Theses and Dissertations