Publications

• The N-Acetylmuramic acid 6-phosphate phosphatase MupP completes the Pseudomonas peptidoglycan recycling pathway leading to intrinsic fosfomycin resistance.

  Borisova M., Gisin J., Mayer C.

  Bacterial cells are encased in and stabilized by a netlike peptidoglycan (PGN) cell wall that undergoes turnover during bacterial growth. PGN turnover fragments are frequently salvaged by the cells via a pathway referred to as PGN recycling. Two different routes for the recycling of the cell wall ... >> More

  Bacterial cells are encased in and stabilized by a netlike peptidoglycan (PGN) cell wall that undergoes turnover during bacterial growth. PGN turnover fragments are frequently salvaged by the cells via a pathway referred to as PGN recycling. Two different routes for the recycling of the cell wall sugar <i>N</i>-acetylmuramic acid (MurNAc) have been recognized in bacteria. In <i>Escherichia coli</i> and related enterobacteria, as well as in most Gram-positive bacteria, MurNAc is recovered via a catabolic route requiring a MurNAc 6-phosphate etherase (MurQ in <i>E. coli</i>) enzyme. However, many Gram-negative bacteria, including <i>Pseudomonas</i> species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the <i>de novo</i> biosynthesis of uridyldiphosphate (UDP)-MurNAc, the first committed precursor of PGN. Bacteria featuring the latter pathway become intrinsically resistant to the antibiotic fosfomycin, which targets the <i>de novo</i> biosynthesis of UDP-MurNAc. We report here the identification and characterization of a phosphatase enzyme, named MupP, that had been predicted to complete the anabolic recycling pathway of <i>Pseudomonas</i> species but has remained unknown so far. It belongs to the large haloacid dehalogenase family of phosphatases and specifically converts MurNAc 6-phosphate to MurNAc. A Δ<i>mupP</i> mutant of <i>Pseudomonas putida</i> was highly susceptible to fosfomycin, accumulated large amounts of MurNAc 6-phosphate, and showed lower levels of UDP-MurNAc than wild-type cells, altogether consistent with a role for MupP in the anabolic PGN recycling route and as a determinant of intrinsic resistance to fosfomycin.<b>IMPORTANCE</b> Many Gram-negative bacteria, but not <i>E. coli</i>, make use of a cell wall salvage pathway that contributes to the pool of UDP-MurNAc, the first committed precursor of cell wall synthesis in bacteria. This salvage pathway is of particular interest because it confers intrinsic resistance to the antibiotic fosfomycin, which blocks <i>de novo</i> UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of <i>P. putida</i> MupP, together with the other enzymes of the anabolic recycling pathway, AnmK, AmgK, and MurU, yields UDP-MurNAc, renders bacteria intrinsically resistant to fosfomycin, and thus may serve as a novel drug target for antimicrobial therapy. << Less

  MBio 8:0-0(2017) [PubMed] [EuropePMC]