Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics

Bouquet, Jaufret; King, D.T.; Vadlamani, Grishma; Benzie, G. R.; Iorga, Bogdan I.; Ide, Daisuke; Adachi, Isao; Kato, Atsushi; Vocadlo, David J.; Mark, Brian L.; Blériot, Yves; Désiré, Jérôme

doi:10.1039/c7ob00838d

Cited by 13 publications

(11 citation statements)

References 31 publications

(29 reference statements)

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“…280 NagZ inhibition achieves modest levels of synergy with β -lactams. 76,77,81,83,114,306–309 . These data suggest that induction of AmpC β -lactamase occurs both by a NagZ-precursor muropeptide and by a NagZ-derived muropeptide.…”

Section: Evolutionary Adaption To the Chemical Imprinting On The Cellmentioning

confidence: 99%

Cell-Wall Recycling of the Gram-Negative Bacteria and the Nexus to Antibiotic Resistance

2018

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The importance of the cell wall to the viability of the bacterium is underscored by the breadth of antibiotic structures that act by blocking key enzymes that are tasked with cell-wall creation, preservation, and regulation. The interplay between cell-wall integrity, and the summoning forth of resistance mechanisms to deactivate cell-wall-targeting antibiotics, involves exquisite orchestration among cell-wall synthesis and remodeling and the detection of and response to the antibiotics through modulation of gene regulation by specific effectors. Given the profound importance of antibiotics to the practice of medicine, the assertion that understanding this interplay is among the most fundamentally important questions in bacterial physiology is credible. The enigmatic regulation of the expression of the AmpC β-lactamase, a clinically significant and highly regulated resistance response of certain Gram-negative bacteria to the β-lactam antibiotics, is the exemplar of this challenge. This review gives a current perspective to this compelling, and still not fully solved, 35-year enigma.

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Section: Evolutionary Adaption To the Chemical Imprinting On The Cellmentioning

confidence: 99%

Cell-Wall Recycling of the Gram-Negative Bacteria and the Nexus to Antibiotic Resistance

2018

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“…Loss of activity of NagZ suppresses AmpC production . Hence, inhibition of NagZ augments the antibiotic efficacy of β‐lactams . Structural reconstruction of all of these observations gives the conclusion that AmpC β‐lactamase correlates with the passage of a particular muropeptide structure from the periplasm to the cytoplasm, through the transmembrane AmpG permease.…”

Section: Abetting the β‐Lactam Antibiotics Against Gram‐negative Bactmentioning

confidence: 99%

“…263 Hence, inhibition of NagZ augments the antibiotic efficacy of β-lactams. [264][265][266][267][268][269][270] Structural reconstruction of all of these observations gives the conclusion that AmpC β-lactamase correlates with the passage of a particular muropeptide structure from the periplasm to the cytoplasm, through the transmembrane AmpG permease. The muropeptide originates by LT-dependent excision from the cell wall.…”

Section: Abetting the β-Lactam Antibiotics Against Gram-negative Bamentioning

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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“…The seven-membered, N -heterocyclic azepane scaffold is a biologically active epitope and useful building block in the construction of novel glycosidase inhibitors [ 1 , 2 , 3 , 4 , 5 ], anticancers [ 6 , 7 , 8 , 9 , 10 ], antidiabetics [ 11 , 12 , 13 , 14 , 15 ], antivirals [ 16 , 17 ] and DNA minor groove-binding agents [ 18 , 19 , 20 ]. In particular, azepanols and oxo-azepines have received much recent attention as useful epitopes in both materials and medicinal chemistry due to the unique flexibility of the seven-membered ring and resultant spatial distribution of oxygen substituents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation

2017

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Substituted seven-membered N-heterocycles are prevalent bioactive epitopes and useful synthons for preparing enzyme inhibitors or molecular recognition systems. To fully exploit the chemical properties of this flexible N-heterocycle scaffold, efficient methods for its diverse functionalization are required. Here we utilize the late-stage oxidation of tetrahydroazepines as an approach to access densely functionalized oxo-azepines in a total of 8 steps and ~30% overall yield from commercially available starting materials. Hydroboration of tetrahydroazepines proceeded with diastereoselectivity in a substrate-dependent manner to yield regioisomeric azepanols before their oxidation to the corresponding oxo-azepines. Regioselectivity of the hydroboration step may be improved moderately by a rhodium catalyst, albeit with loss of conversion to a competing hydrogenation pathway. Overall our method allows efficient access to azepanols and oxo-azepines as versatile epitopes and synthons with a high degree of diastereoselectivity and moderate regioselectivity.

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Selective trihydroxylated azepane inhibitors of NagZ, a glycosidase involved in Pseudomonas aeruginosa resistance to β-lactam antibiotics

Cited by 13 publications

References 31 publications

Cell-Wall Recycling of the Gram-Negative Bacteria and the Nexus to Antibiotic Resistance

Cell-Wall Recycling of the Gram-Negative Bacteria and the Nexus to Antibiotic Resistance

Constructing and deconstructing the bacterial cell wall

Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation

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