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Angew Chem Int Ed Engl. 2016 Feb 5;55(6):2210-2. doi: 10.1002/anie.201510057. Epub 2015 Dec 28.

Total Synthesis and Activity of the Metallo-β-lactamase Inhibitor Aspergillomarasmine A.

Author information

1
Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada.
2
Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. capretta@mcmaster.ca.
3
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. capretta@mcmaster.ca.
4
Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. wrightge@mcmaster.ca.

Abstract

Resistance to β-lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal-dependent activation of a water molecule. Serine β-lactamases are countered in the clinic by several codrugs that inhibit these enzymes, thereby rescuing antibiotic action. There are no equivalent inhibitors of metallo-β-lactamases in clinical use, but the fungal secondary metabolite aspergillomarasmine A has recently been identified as a potential candidate for such a codrug. Herein we report the synthesis of aspergillomarasmine A. The synthesis enabled confirmation of the stereochemical configuration of the compound and offers a route for the synthesis of derivatives in the future.

KEYWORDS:

antibiotic resistance; configuration determination; inhibitors; metallo-β-lactamases; total synthesis

PMID:
26709849
DOI:
10.1002/anie.201510057
[Indexed for MEDLINE]

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