A mechanism-based GlcNAc-inspired cyclophellitol inactivator of the peptidoglycan recycling enzyme NagZ reverses resistance to β-lactams in Pseudomonas aeruginosa

Louisa A Ho; Judith L Winogrodzki; Aleksandra W Debowski; Zarina Madden; David J Vocadlo; Brian L Mark; Keith A Stubbs

doi:10.1039/c8cc05281f

A mechanism-based GlcNAc-inspired cyclophellitol inactivator of the peptidoglycan recycling enzyme NagZ reverses resistance to β-lactams in Pseudomonas aeruginosa

Chem Commun (Camb). 2018 Sep 25;54(75):10630-10633. doi: 10.1039/c8cc05281f. Epub 2018 Sep 4.

Authors

Louisa A Ho¹, Judith L Winogrodzki², Aleksandra W Debowski³, Zarina Madden⁴, David J Vocadlo⁴, Brian L Mark², Keith A Stubbs¹

Affiliations

¹ School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. keith.stubbs@uwa.edu.au.
² Department of Microbiology, University of Manitoba, Winnipeg, Manitoba R3T2N2, Canada. Brian.mark@umanitoba.ca.
³ School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia. keith.stubbs@uwa.edu.au and School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
⁴ Department of Chemistry, Simon Fraser University, Burnaby, BC V5A1S6, Canada.

PMID: 30178799
DOI: 10.1039/c8cc05281f

Abstract

The development of a potent mechanism-based inactivator of NagZ, an enzyme critical to the production of inducible AmpC β-lactamase in Gram-negative bacteria, is presented. This inactivator significantly reduces MIC values for important β-lactams against a clinically relevant strain of Pseudomonas aeruginosa.

MeSH terms

Acetylglucosaminidase / antagonists & inhibitors*
Acetylglucosaminidase / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology*
Aztreonam / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Burkholderia cenocepacia / enzymology
Ceftazidime / pharmacology
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Epoxy Compounds / chemical synthesis
Epoxy Compounds / metabolism
Epoxy Compounds / pharmacology*
Humans
Imipenem / pharmacology
Microbial Sensitivity Tests
Protein Binding
Pseudomonas aeruginosa / enzymology
Pseudomonas aeruginosa / metabolism*
beta-Lactam Resistance / drug effects*
beta-N-Acetylhexosaminidases / antagonists & inhibitors

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Epoxy Compounds
Imipenem
Ceftazidime
alpha-N-acetyl-D-glucosaminidase
hexosaminidase C
Acetylglucosaminidase
beta-N-Acetylhexosaminidases
Aztreonam