Enolpyruvate transferase MurAAA149E, identified during adaptation of Enterococcus faecium to daptomycin, increases stability of MurAA–MurG interaction

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dc.citation.articleNumber102912en_US
dc.citation.issueNumber3en_US
dc.citation.journalTitleJournal of Biological Chemistryen_US
dc.citation.volumeNumber299en_US
dc.contributor.authorZhou, Yueen_US
dc.contributor.authorUtama, Budien_US
dc.contributor.authorPratap, Shivendraen_US
dc.contributor.authorSupandy, Adelineen_US
dc.contributor.authorSong, Xinhaoen_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorMehta, Heer H.en_US
dc.contributor.authorArias, Cesar A.en_US
dc.contributor.authorShamoo, Yousifen_US
dc.date.accessioned2023-03-10T19:04:07Zen_US
dc.date.available2023-03-10T19:04:07Zen_US
dc.date.issued2023en_US
dc.description.abstractDaptomycin (DAP) is an antibiotic frequently used as a drug of last resort against vancomycin-resistant enterococci. One of the major challenges when using DAP against vancomycin-resistant enterococci is the emergence of resistance, which is mediated by the cell-envelope stress system LiaFSR. Indeed, inhibition of LiaFSR signaling has been suggested as a strategy to “resensitize” enterococci to DAP. In the absence of LiaFSR, alternative pathways mediating DAP resistance have been identified, including adaptive mutations in the enolpyruvate transferase MurAA (MurAAA149E), which catalyzes the first committed step in peptidoglycan biosynthesis; however, how these mutations confer resistance is unclear. Here, we investigated the biochemical basis for MurAAA149E-mediated adaptation to DAP to determine whether such an alternative pathway would undermine the potential efficacy of therapies that target the LiaFSR pathway. We found cells expressing MurAAA149E had increased susceptibility to glycoside hydrolases, consistent with decreased cell wall integrity. Furthermore, structure–function studies of MurAA and MurAAA149E using X-ray crystallography and biochemical analyses indicated only a modest decrease in MurAAA149E activity, but a 16-fold increase in affinity for MurG, which performs the last intracellular step of peptidoglycan synthesis. Exposure to DAP leads to mislocalization of cell division proteins including MurG. In Bacillus subtilis, MurAA and MurG colocalize at division septa and, thus, we propose MurAAA149E may contribute to DAP nonsusceptibility by increasing the stability of MurAA–MurG interactions to reduce DAP-induced mislocalization of these essential protein complexes.en_US
dc.identifier.citationZhou, Yue, Utama, Budi, Pratap, Shivendra, et al.. "Enolpyruvate transferase MurAAA149E, identified during adaptation of Enterococcus faecium to daptomycin, increases stability of MurAA–MurG interaction." <i>Journal of Biological Chemistry,</i> 299, no. 3 (2023) Elsevier: https://doi.org/10.1016/j.jbc.2023.102912.en_US
dc.identifier.digital1-s2-0-S0021925823000443-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.jbc.2023.102912en_US
dc.identifier.urihttps://hdl.handle.net/1911/114487en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/)en_US
dc.titleEnolpyruvate transferase MurAAA149E, identified during adaptation of Enterococcus faecium to daptomycin, increases stability of MurAA–MurG interactionen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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