The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

ABSTRACT 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 cel...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Marina Borisova, Jonathan Gisin, Christoph Mayer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/683cd1e71b76433d8d33e0b07b4a67a2
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:683cd1e71b76433d8d33e0b07b4a67a2
record_format	dspace
spelling	oai:doaj.org-article:683cd1e71b76433d8d33e0b07b4a67a22021-11-15T15:51:00ZThe <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance10.1128/mBio.00092-172150-7511https://doaj.org/article/683cd1e71b76433d8d33e0b07b4a67a22017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00092-17https://doaj.org/toc/2150-7511ABSTRACT 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 N-acetylmuramic acid (MurNAc) have been recognized in bacteria. In Escherichia coli 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 E. coli) enzyme. However, many Gram-negative bacteria, including Pseudomonas species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the de novo 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 de novo 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 Pseudomonas 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 ΔmupP mutant of Pseudomonas putida 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. IMPORTANCE Many Gram-negative bacteria, but not E. coli, 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 de novo UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of P. putida. 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.Marina BorisovaJonathan GisinChristoph MayerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Marina Borisova Jonathan Gisin Christoph Mayer The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
description	ABSTRACT 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 N-acetylmuramic acid (MurNAc) have been recognized in bacteria. In Escherichia coli 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 E. coli) enzyme. However, many Gram-negative bacteria, including Pseudomonas species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the de novo 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 de novo 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 Pseudomonas 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 ΔmupP mutant of Pseudomonas putida 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. IMPORTANCE Many Gram-negative bacteria, but not E. coli, 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 de novo UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of P. putida. 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.
format	article
author	Marina Borisova Jonathan Gisin Christoph Mayer
author_facet	Marina Borisova Jonathan Gisin Christoph Mayer
author_sort	Marina Borisova
title	The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
title_short	The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
title_full	The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
title_fullStr	The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
title_full_unstemmed	The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance
title_sort	<italic toggle="yes">n</italic>-acetylmuramic acid 6-phosphate phosphatase mupp completes the <italic toggle="yes">pseudomonas</italic> peptidoglycan recycling pathway leading to intrinsic fosfomycin resistance
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/683cd1e71b76433d8d33e0b07b4a67a2
work_keys_str_mv	AT marinaborisova theitalictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance AT jonathangisin theitalictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance AT christophmayer theitalictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance AT marinaborisova italictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance AT jonathangisin italictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance AT christophmayer italictoggleyesnitalicacetylmuramicacid6phosphatephosphatasemuppcompletestheitalictoggleyespseudomonasitalicpeptidoglycanrecyclingpathwayleadingtointrinsicfosfomycinresistance
_version_	1718427402433986560

The <italic toggle="yes">N</italic>-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the <italic toggle="yes">Pseudomonas</italic> Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

Ejemplares similares