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Issue 1, 2016
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Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

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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 (compound 1), that inhibited the acetylation of aminoglycosides in vitro with IC50 values of 39.7 and 34.9 μM when the aminoglycoside substrates assayed were kanamycin A or amikacin, respectively. The growth of an amikacin-resistant Acinetobacter baumannii clinical strain was inhibited in the presence of a combination of amikacin and compound 1.

Graphical abstract: Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

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Publication details

The article was received on 30 Jul 2015, accepted on 03 Nov 2015 and first published on 16 Nov 2015


Article type: Concise Article
DOI: 10.1039/C5MD00316D
Author version available: Download Author version (PDF)
Citation: Med. Chem. Commun., 2016,7, 184-189
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    Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

    K. Chiem, S. Jani, B. Fuentes, D. L. Lin, M. E. Rasche and M. E. Tolmasky, Med. Chem. Commun., 2016, 7, 184
    DOI: 10.1039/C5MD00316D

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