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