title: Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones.
abstract: Aminoglycoside-2"-O-nucleotidyltransferase ANT(2")-Ia is an aminoglycoside resistance enzyme prevalent among Gram-negative bacteria, and is one of the most common determinants of enzyme-dependant aminoglycoside-resistance. The following report outlines the use of our recently described oxidopyrylium cycloaddition/ring-opening strategy in the synthesis and profiling of a library of synthetic α-hydroxytropolones against ANT(2")-Ia. In addition, we show that two of these synthetic constructs are capable of rescuing gentamicin activity against ANT-(2")-Ia-expressing bacteria.
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Hirsch
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8N 4K1, Canada.
authors.forename: Georgina
authors.initials: G
authors.lastname: Cox
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: D'Erasmo
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8N 4K1, Canada.
authors.forename: Tushar
authors.initials: T
authors.lastname: Shakya
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Meck
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States.
authors.forename: Noushad
authors.initials: N
authors.lastname: Mohd
authors.affiliation: M. G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8N 4K1, Canada.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States; Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, United States. Electronic address: rpmurelli@brooklyn.cuny.edu.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Murelli
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects*; D005839:Gentamicins / Q000494:pharmacology*; D008956:Models, Chemical; D015394:Molecular Structure; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014334:Tropolone / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D014334:Tropolone; D009713:Nucleotidyltransferases; C020565:gentamicin 2''-nucleotidyltransferase
keywords: Aminoglycoside-2″-O-nucleotidyltransferase; Aminoglycosides; Bacterial Resistance; Gentamicin; α-Hydroxytropolones