Mathematics Faculty Articles

Title

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.

Comments

©2018 Elsevier B.V. and International Society of Chemotherapy

Additional Comments

National Institute of Allergy and Infectious Diseases Public Health Service Grant #: 2R15AI047115-04

DOI

10.1016/j.ijantimicag.2018.01.019

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