Inactivation of the Glycoside Hydrolase NagZ Attenuates Antipseudomonal β-Lactam Resistance in
            <i>Pseudomonas aeruginosa</i>

Asgarali, Azizah; Stubbs, Keith A.; Oliver, Antonio; Vocadlo, David J.; Mark, Brian L.

doi:10.1128/aac.01617-08

Cited by 61 publications

(76 citation statements)

References 50 publications

(67 reference statements)

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“…Both AmpD and NagZ have the ability to catalyze the hydrolysis of anhydromuropeptides in the cytoplasm (6,39). Deletion of the ampD gene produces a negligible impact on the S. oneidensis resistance to ␤-lactams; however, this may be due to the presence of the more robust enzyme NagZ.…”

Section: Nagz Functionally Overwhelms Ampd In Induction Of Blaamentioning

confidence: 82%

Distinct Roles of Major Peptidoglycan Recycling Enzymes in β-Lactamase Production in Shewanella oneidensis

Yin

Mao

et al. 2014

Antimicrob Agents Chemother

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c ␤-Lactam antibiotics were the earliest discovered and are the most widely used group of antibiotics that work by inactivating penicillin-binding proteins to inhibit peptidoglycan biosynthesis. As one of the most efficient defense strategies, many bacteria produce ␤-lactam-degrading enzymes, ␤-lactamases, whose biochemical functions and regulation have been extensively studied. A signal transduction pathway for ␤-lactamase induction by ␤-lactam antibiotics, consisting of the major peptidoglycan recycling enzymes and the LysR-type transcriptional regulator, AmpR, has been recently unveiled in some bacteria. Because inactivation of some of these proteins, especially the permease AmpG and the ␤-hexosaminidase NagZ, results in substantially elevated susceptibility to the antibiotics, these have been recognized as potential therapeutic targets. Here, we show a contrasting scenario in Shewanella oneidensis, in which the homologue of AmpR is absent. Loss of AmpG or NagZ enhances ␤-lactam resistance drastically, whereas other identified major peptidoglycan recycling enzymes are dispensable. Moreover, our data indicate that there exists a parallel signal transduction pathway for ␤-lactamase induction, which is independent of either AmpG or NagZ.

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Section: Nagz Functionally Overwhelms Ampd In Induction Of Blaamentioning

confidence: 82%

Distinct Roles of Major Peptidoglycan Recycling Enzymes in β-Lactamase Production in Shewanella oneidensis

Yin

Mao

et al. 2014

Antimicrob Agents Chemother

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“…Mutations in nagZ result in low levels of ampC expression that enhances the susceptibility to b-lactam antibiotics [206,207]. Deletion of nagZ also reversed the resistance due to ampC hyper-expression in ampD and dacB mutants [207].…”

Section: Cell-wall Recycling and Antibiotic Resistancementioning

confidence: 99%

“…NagZ (PA3005) is a b-N-acetylglucosaminidase that removes GlcNAc to generate the 1,6-anhydromuropeptides, the putative activators of AmpR that are required for the induction of ampC [206]. Mutations in nagZ result in low levels of ampC expression that enhances the susceptibility to b-lactam antibiotics [206,207].…”

Section: Cell-wall Recycling and Antibiotic Resistancementioning

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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“…Attenuation has been achieved in a model system of E. coli harboring a plasmid encoding an ampC-ampR operon, 16 and more recently in the opportunistic pathogen P. aeruginosa. 29 The most selective inhibitor found to date is $100-fold selective for NagZ over the human b-hexosaminidase isoenzymes and O-GlcNAcase. This derivative of PUGNAc, N-valeryl-PUGNAc [ Fig.…”

mentioning

confidence: 99%

Insight into a strategy for attenuating AmpC‐mediated β‐lactam resistance: Structural basis for selective inhibition of the glycoside hydrolase NagZ

Balcewich

Stubbs

et al. 2009

Protein Science

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NagZ is an exo-N-acetyl-b-glucosaminidase, found within Gram-negative bacteria, that acts in the peptidoglycan recycling pathway to cleave N-acetylglucosamine residues off peptidoglycan fragments. This activity is required for resistance to cephalosporins mediated by inducible AmpC b-lactamase. NagZ uses a catalytic mechanism involving a covalent glycosyl enzyme intermediate, unlike that of the human exo-N-acetyl-b-glucosaminidases: O-GlcNAcase and the b-hexosaminidase isoenzymes. These latter enzymes, which remove GlcNAc from glycoconjugates, use a neighboring-group catalytic mechanism that proceeds through an oxazoline intermediate. Exploiting these mechanistic differences we previously developed 2-N-acyl derivatives of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), which selectively inhibits NagZ over the functionally related human enzymes and attenuate antibiotic resistance in Gram-negatives that harbor inducible AmpC. To understand the structural basis for the selectivity of these inhibitors for NagZ, we have determined its crystallographic structure in complex with N-valeryl-PUGNAc, the most selective known inhibitor of NagZ over both the human b-hexosaminidases and O-GlcNAcase. The selectivity stems from the five-carbon acyl chain of N-valeryl-PUGNAc, which we found ordered within the enzyme active site. In contrast, a structure determination of a human O-GlcNAcase homologue bound to a related inhibitor N-butyryl-PUGNAc, which bears a four-carbon chain and is selective for both NagZ and O-GlcNAcase over the human b-hexosamnidases, reveals that this inhibitor induces several conformational changes in the active site of this O-GlcNAcase homologue. A comparison of these complexes, and with the human b-hexosaminidases, reveals how selectivity for NagZ can be engineered by altering the 2-N-acyl substituent of PUGNAc to develop inhibitors that repress AmpC mediated b-lactam resistance.

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Inactivation of the Glycoside Hydrolase NagZ Attenuates Antipseudomonal β-Lactam Resistance in Pseudomonas aeruginosa

Cited by 61 publications

References 50 publications

Distinct Roles of Major Peptidoglycan Recycling Enzymes in β-Lactamase Production in Shewanella oneidensis

Distinct Roles of Major Peptidoglycan Recycling Enzymes in β-Lactamase Production in Shewanella oneidensis

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

Insight into a strategy for attenuating AmpC‐mediated β‐lactam resistance: Structural basis for selective inhibition of the glycoside hydrolase NagZ

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