Mathematics Faculty Articles
Identification of a Small Molecule Inhibitor of the Aminoglycoside 6'- N -acetyltransferase Type Ib [AAC(6')-Ib] Using Mixture-Based Combinatorial Libraries
Document Type
Article
Publication Date
4-30-2018
Publication Title
International Journal of Antimicrobial Agents
Keywords
Acetyltransferase, Aminoglycoside, Enterobacteriaceae, ESKAPE, Hospital infection, Combinatorial libraries
ISSN
0924-8579
Volume
51
Issue/No.
5
First Page
752
Last Page
761
Abstract
The aminoglycoside, 6′-N-acetyltransferase type Ib [AAC(6')-Ib] is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens and confers resistance to clinically relevant aminoglycosides, including amikacin. This enzyme is therefore an ideal target for enzymatic inhibitors that could overcome resistance to aminoglycosides. The search for inhibitors was carried out using mixture-based combinatorial libraries, the scaffold ranking approach, and the positional scanning strategy. A library with high inhibitory activity had pyrrolidine pentamine scaffold and was selected for further analysis. This library contained 738,192 compounds with functionalities derived from 26 different amino acids (R1, R2 and R3) and 42 different carboxylic acids (R4) in four R–group functionalities. The most active compounds all contained S-phenyl (R1 and R3) and S-hydromethyl (R2) functionalities at three locations and differed at the R4 position. The compound containing 3-phenylbutyl at R4 (compound 206) was a robust enzymatic inhibitor in vitro, in combination with amikacin it potentiated the inhibition of growth of three resistant bacteria in culture, and it improved survival when used as treatment of Galleria mellonella infected with aac(6')-Ib -harboring Klebsiella pneumoniae and Acinetobacter baumannii strains.
Additional Comments
National Institute of Allergy and Infectious Diseases Public Health Service Grant #: 2R15AI047115-04
NSUWorks Citation
Tran, Tung; Chiem, Kevin; Jani, Saumya; Arivett, Brock A.; Lin, David L.; Lad, Rupali; Jimenez, Veronica; Farone, Mary B.; Debevac, Ginamarie; Santos, Radleigh; Giulianotti, Marc; Pinilla, Clemencia; and Tolmasky, Marcelo E., "Identification of a Small Molecule Inhibitor of the Aminoglycoside 6'- N -acetyltransferase Type Ib [AAC(6')-Ib] Using Mixture-Based Combinatorial Libraries" (2018). Mathematics Faculty Articles. 218.
https://nsuworks.nova.edu/math_facarticles/218
DOI
10.1016/j.ijantimicag.2018.01.019
Comments
©2018 Elsevier B.V. and International Society of Chemotherapy