Identification of MupP as a New Peptidoglycan Recycling Factor and Antibiotic Resistance Determinant in
            <i>Pseudomonas aeruginosa</i>

Fumeaux, Coralie; Bernhardt, Thomas G.

doi:10.1128/mbio.00102-17

Cited by 30 publications

(46 citation statements)

References 55 publications

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“…This route renders these bacteria intrinsically resistant to fosfomycin, possibly because of a reduction of the UDP-MurNAc pool level, which also is consistent with the observed β-lactam resistance phenotype shown in the accompanying report (25). Thus, MupP and the entire anabolic recycling pathway may serves as a novel target for antibacterial agents, particularly in combination therapy against Gram-negative pathogens.…”

Section: Discussionsupporting

confidence: 88%

“…In this vein, it is very compelling that Thomas Bernhardt’s group independently discovered an ortholog of mupP (PA3172) in P. aeruginosa by genetic screening for mutants affected in AmpC β-lactamase induction. They showed that deletion of mupP or another gene of the PGN recycling pathway causes elevated expression of AmpC and hence increased resistance to β-lactam antibiotics, which was explained by reduced steady-state levels of UDP-MurNAc-pentapeptide (25). …”

Section: Discussionmentioning

confidence: 99%

“…Notably, the enzyme MupP (PA3172) was independently discovered in P. aeruginosa by genetic screening by the group of Thomas Bernhardt. They additionally link MupP and PGN recycling with a modulating influence on AmpC β-lactamase resistance (25). …”

Section: Introductionmentioning

confidence: 99%

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The N -Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

Borisova

Gisin

Mayer

2017

mBio

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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The N -Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

Borisova

Gisin

Mayer

2017

mBio

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“…In P. aeruginosa, an AnmK homologue PA0666 phosphorylates anhMurNAc to form MurNAc-6-P; subsequently, the phosphate is removed by MupP (PA3172) resulting in MurNAc [174][175][176][177]. MurNAc is further processed by two enzymes AmgK (PA0596) and MurU (PA0597) unique to pseudomonads encoded in the same operon [178].…”

Section: Convergence Of Recycling and Biosynthesismentioning

confidence: 99%

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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The bacterial cell-wall that forms a protective layer over the inner membrane is called the murein sacculus -a tightly crosslinked peptidoglycan mesh unique to bacteria. Cell-wall synthesis and recycling are critical cellular processes essential for cell growth, elongation and division. Both de novo synthesis and recycling involve an array of enzymes across all cellular compartments, namely the outer membrane, periplasm, inner membrane and cytoplasm. Due to the exclusivity of peptidoglycan in the bacterial cell-wall, these players are the target of choice for many antibacterial agents. Our current understanding of cell-wall biochemistry and biogenesis in Gram-negative organisms stems mostly from studies of Escherichia coli. An incomplete knowledge on these processes exists for the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. In this review, cell-wall synthesis and recycling in the various cellular compartments are compared and contrasted between E. coli and P. aeruginosa. Despite the fact that there is a remarkable similarity of these processes between the two bacterial species, crucial differences alter their resistance to b-lactams, fluoroquinolones and aminoglycosides. One of the common mediators underlying resistance is the amp system whose mechanism of action is closely associated with the cell-wall recycling pathway. The activation of amp genes results in expression of AmpC blactamase through its cognate regulator AmpR which further regulates multi-drug resistance. In addition, other cell-wall recycling enzymes also contribute to antibiotic resistance. This comprehensive summary of the information should spawn new ideas on how to effectively target cell-wall processes to combat the growing resistance to existing antibiotics.

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“…The allosteric control of S. aureus PBP2a (and perhaps of other PBPs) may well be to synchronize loop opening of the active site with protein translocation, but this explanation is almost certainly an oversimplification. The narrative presented here conceptualizes a two‐dimensional pathway for the peptidoglycan construction and deconstruction by P. aeruginosa when the realities of both AmpR regulation and cell‐wall biosynthesis are multidimensional . Yet this reductionism led to the deduction that the allosteric regulation of PBP2a is a solid basis for small molecule antibacterial discovery, and the parsing of the specificity of bulgecin as a selective inhibitor within the lytic transglycosylase family of P. aeruginosa .…”

Section: Resultsmentioning

confidence: 99%

Constructing and deconstructing the bacterial cell wall

Fisher

Mobashery

2019

Protein Science

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The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell‐wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre‐eminent class of antibiotics—the β‐lactams, exemplified by the penicillins and cephalosporins—from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β‐lactams is bacterial cell‐wall destruction. In the monoderm (single membrane, Gram‐positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β‐lactam‐unreactive transpeptidase enzyme that functions in cell‐wall construction. In the diderm (dual membrane, Gram‐negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β‐lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell‐wall construction and cell‐wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β‐lactams. This review summarizes how the β‐lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

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Identification of MupP as a New Peptidoglycan Recycling Factor and Antibiotic Resistance Determinant in Pseudomonas aeruginosa

Cited by 30 publications

References 55 publications

The N -Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

The N -Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Constructing and deconstructing the bacterial cell wall

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