title: Total Synthesis and Activity of the Metallo-β-lactamase Inhibitor Aspergillomarasmine A.
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.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada.
authors.forename: Kalinka
authors.initials: K
authors.lastname: Koteva
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: King
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. capretta@mcmaster.ca.|Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. capretta@mcmaster.ca.
authors.forename: Alfredo
authors.identifier: http://orcid.org/0000-0002-8832-0011
authors.initials: A
authors.lastname: Capretta
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main Street West, Hamilton, ON, Canada. wrightge@mcmaster.ca.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001230:Aspergillus / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D065093:beta-Lactamase Inhibitors; D001224:Aspartic Acid; C069862:aspergillomarasmine A; D001618:beta-Lactamases
keywords: antibiotic resistance; configuration determination; inhibitors; metallo-β-lactamases; total synthesis