title: Identification of an Inhibitor of the Aminoglycoside 6'-N-Acetyltransferase type Ib [AAC(6')-Ib] by Glide Molecular Docking.
abstract: The aminoglycoside 6'-N-acetyltransferase type Ib, AAC(6')-Ib, confers resistance to clinically relevant aminoglycosides and is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens. An alternative to counter the action of this enzyme is the development of inhibitors. Glide is a computational strategy for rapidly docking ligands to protein sites and estimating their binding affinities. We docked a collection of 280,000 compounds from 7 sub-libraries of the Chembridge library as ligands to the aminoglycoside binding site of AAC(6')-Ib. We identified a compound, 1-[3-(2-aminoethyl)benzyl]-3-(piperidin-1-ylmethyl)pyrrolidin-3-ol (compound1), that inhibited the acetylation of aminoglycosidesin vitrowith IC50values of 39.7 and 34.9 µM when the aminoglycoside substrates assayed were kanamycin A or amikacin, respectively. The growth of an amikacin-resistantAcinetobacter baumanniiclinical strain was inhibited in the presence of a combination of amikacin and compound1.
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chiem
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: Saumya
authors.initials: S
authors.lastname: Jani
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: Brooke
authors.initials: B
authors.lastname: Fuentes
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Lin
authors.affiliation: Center for Applied Biotechnology Studies, Department of Chemistry and Biochemistry, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: Madeline E
authors.initials: ME
authors.lastname: Rasche
authors.affiliation: Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92834-6850, United States.
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Tolmasky