Synthesis and structure-activity relationships of truncated bisubstrate inhibitors of aminoglycoside 6'-N-acetyltransferases

Feng Gao; Xuxu Yan; Tushar Shakya; Oliver M Baettig; Samia Ait-Mohand-Brunet; Albert M Berghuis; Gerard D Wright; Karine Auclair

doi:10.1021/jm060732n

Synthesis and structure-activity relationships of truncated bisubstrate inhibitors of aminoglycoside 6'-N-acetyltransferases

J Med Chem. 2006 Aug 24;49(17):5273-81. doi: 10.1021/jm060732n.

Authors

Feng Gao¹, Xuxu Yan, Tushar Shakya, Oliver M Baettig, Samia Ait-Mohand-Brunet, Albert M Berghuis, Gerard D Wright, Karine Auclair

Affiliation

¹ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 2K6, Canada.

PMID: 16913716
DOI: 10.1021/jm060732n

Abstract

Truncated aminoglycoside-coenzyme A bisubstrate analogues were efficiently prepared using a convergent approach where the amine and the thiol are coupled in one pot with the addition of a linker, without the need for protecting groups. These derivatives were tested for their effect on the activity of the resistance-causing enzyme aminoglycoside 6'-N-acetyltransferase Ii, and key structure-activity relationships are reported. Moreover, one of the inhibitors is able to block aminoglycoside resistance in cells expressing this enzyme.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyltransferases / antagonists & inhibitors*
Aminoglycosides / chemical synthesis*
Aminoglycosides / chemistry
Aminoglycosides / pharmacology*
Coenzyme A / chemistry*
Enterococcus faecium / drug effects
Enterococcus faecium / growth & development
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Kanamycin / pharmacology
Microbial Sensitivity Tests
Molecular Conformation
Stereoisomerism
Structure-Activity Relationship

Substances

Aminoglycosides
Enzyme Inhibitors
Kanamycin
Acetyltransferases
aminoglycoside N(6')-acetyltransferase
Coenzyme A