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

• DOI: 10.1016/j.jbc.2023.102912
• Publication Date: 2023-01-14T15:31:25Z
• Authors: Yue Zhou; Budi Utama; Shivendra Pratap; Adeline Supandy; Xinhao Song; Truc T. Tran; Heer H. Mehta; Cesar A. Arias; Yousif Shamoo
• Keywords: Daptomycin; Enterococcus faecium; Transferase

Daptomycin (DAP) is an antibiotic frequently used as a drug of last resort against vancomycin-resistant enterococci. One the major challenges when using DAP enterococci emergence resistance, which mediated by cell-envelope stress system LiaFSR. Indeed, inhibition LiaFSR signaling has been suggested strategy to "resensitize" DAP. In absence LiaFSR, alternative pathways mediating resistance have identified, including adaptive mutations in enolpyruvate transferase MurAA (MurAAA149E), catalyzes first committed step peptidoglycan biosynthesis; however, how these confer unclear. Here, we investigated biochemical basis for MurAAA149E-mediated adaptation determine whether such pathway would undermine potential efficacy therapies that target pathway. We found cells expressing MurAAA149E had increased susceptibility glycoside hydrolases, consistent with decreased cell wall integrity. Furthermore, structure-function studies and X-ray crystallography analyses indicated only modest decrease activity, but 16-fold increase affinity MurG, performs intracellular synthesis. Exposure leads mislocalization division proteins MurG. Bacillus subtilis, MurG colocalize at septa and, thus, propose may contribute nonsusceptibility increasing stability MurAA-MurG interactions reduce DAP-induced essential protein complexes.