Selective trihydroxyazepane NagZ inhibitors increase sensitivity of Pseudomonas aeruginosa to β-lactams

Mondon, Martine; Hur, Soo Young; Vadlamani, Grishma; Rodrigues, Prerana; Tsybina, Polina; Oliver, Antonio; Mark, Brian L.; Vocadlo, David J.; Blériot, Yves

doi:10.1039/c3cc46646a

Cited by 37 publications

(32 citation statements)

References 34 publications

(35 reference statements)

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“…Hence, the anhydroMurNAc structure engaging AmpR has an intact peptide stem. The fourth observation is that small molecule iminosaccharide inhibition of NagZ reduces AmpC-dependent resistance in many (but not all: in S. maltophilia for example, there are two ligands only one of which is NagZ-dependent [92]) of the Gram-negative bacteria with amp systems[12, 104–106]. As summarized in Scheme 2, these observations are interpreted in terms of structure 8c (anhydroMurNAc-pentapeptide) as the signal structure for β-lactamase induction (the co-inducer that derepresses ampC ).…”

Section: The Identity Of the Muropeptide Messenger Controlling Amprmentioning

confidence: 99%

The sentinel role of peptidoglycan recycling in the β-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa

Fisher

Mobashery

2014

Bioorganic Chemistry

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The peptidoglycan is the structural polymer of the bacterial cell envelope. In contrast to an expectation of a structural stasis for this polymer, during the growth of the Gram-negative bacterium this polymer is in a constant state of remodeling and extension. Our current understanding of this peptidoglycan “turnover” intertwines with the deeply related phenomena of the liberation of small peptidoglycan segments (muropeptides) during turnover, the presence of dedicated recycling pathways for reuse of these muropeptides, β-lactam inactivation of specific penicillin-binding proteins as a mechanism for the perturbation of the muropeptide pool, and this perturbation as a controlling mechanism for signal transduction leading to the expression of β-lactamase(s) as a key resistance mechanism against the β-lactam antibiotics. The nexus for many of these events is the control of the AmpR transcription factor by the composition of the muropeptide pool generated during peptidoglycan recycling. In this review we connect the seminal observations of the past decades to new observations that resolve some, but certainly not all, of the key structures and mechanisms that connect to AmpR.

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Section: The Identity Of the Muropeptide Messenger Controlling Amprmentioning

confidence: 99%

The sentinel role of peptidoglycan recycling in the β-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa

Fisher

Mobashery

2014

Bioorganic Chemistry

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“…Based upon these findings, to increase the bacterial susceptibility to b-lactams, small molecule inhibitors gluco-nagstatin, LOGNAc and PUGNAc which are analogous to the NagZ substrates that have oxocarbenium-like transition states have been synthesized (Fig. 3) [208,209]. Among the three, PUGNAc was the most potent inhibitor of b-N-acetylglucosaminidase [210].…”

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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“…We have contributed to the development of a new class of seven‐membered iminosugars, the polyhydroxylated azepanes, that inhibit glycosidases in a competitive manner . Introduction of a NHAc group on the azepane ring as in AzeNAc 5 led to potent and broadly effective inhibitors of hexosaminidases, including OGA and NagZ (Figure ). AzeNAc 5 was exploited here to synthesize a set of multivalent iminosugar clusters with varied valencies that are based on the trihydroxylated acetamidoazepane moiety.…”

Section: Resultsmentioning

confidence: 99%

Multivalency To Inhibit and Discriminate Hexosaminidases

Álvarez-Dorta

King

Legigan

et al. 2017

Chemistry A European J

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Selective trihydroxyazepane NagZ inhibitors increase sensitivity of Pseudomonas aeruginosa to β-lactams

Cited by 37 publications

References 34 publications

The sentinel role of peptidoglycan recycling in the β-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa

The sentinel role of peptidoglycan recycling in the β-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa

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

Multivalency To Inhibit and Discriminate Hexosaminidases

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