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Inhibitors of aminoglycoside acetyltransferases as agents
to mitigate resistance to aminoglycoside antibiotics
Overview:
A common pathway associated with resistance to antimicrobial aminoglycosides is the bacterial
expression of drug-modifying enzymes such as adenylyltransferases, phosphoryltransferases, and
acetyltransferases. The intellectual property relates to novel competitive inhibitors of Aminoglycoside 6’N-acetyltransferase. The compounds of the invention possess inhibitory activity against aminoglycoside
6’-N-acetyltransferase type Ii (AAC6’Ii) that is chromosomally encoded in E. faecium. Enterococcus
faecium is one of the leading causes of hospital-acquired infections. The chemical genus forms the basis
of compounds that potentially exhibit dual activity as antibacterial agents and bacterial 6’-Nacetyltransferase inhibitors. The high resolution bimolecular crystal structure of key inhibitors complexed
with the target enzyme has been solved thereby providing the opportunity for rapid chemical
optimization.
Medical need:
Aminoglycoside antibitotics remain important and at times indispensable treatment options in human
chemotherapy as well as veterinary medicine. There is now a global public health concern due to an
exponential rise in bacterial resistance. The problem is particularly acute in critical care settings. The
Centers for Disease Control and Prevention (CDC) estimate that over two million hospital-acquired
infections occur each year causing extended hospital stays and approximately 88,000 deaths in the
United States alone. The CDC further reports that in 2002 an estimated 102,000 cases (57%) of the
Staphylococcus aureus found in U.S. hospitals were MRSA and the underlying cause of 12,000 deaths
and US $9.5B in hospital costs. The burden on healthcare stemming from nosocomial infections is in the
order of US $5 billion in the U.S. alone. Accordingly there is a strong need to overcome the MDR
phenotype.
Validation :
Figure 1: Shows the bimolecular crystallographic structure of E. Faecium AAC(6’)-Ii dimer
complexed with inhibitor 11.
Feng Gao, Xuxu Yan, Oliver M. Baettig,
Albert M. Berghuis, and Karine Auclair;
Angew. Chem. Int. Ed. 2005, 44, 6859–6862
Compound 11 Ki= 43 + 23 nM
Inventors: Auclair Karine; Vong Kenward
Profile:
Dr. Karine Auclair Ph.D.
Associate Professor Department of Chemistry; McGill University.
B.Sc . Chemistry; L’Université de Québec à Chicoutimi
Ph.D. Organic Chemistry; University of Alberta.
Post Doctoral: University of California, San Francisco
http://auclair-group.mcgill.ca/
Our research takes advantage of chemical tools to study and manipulate biological systems. We
are especially interested in antibiotic resistance, P450 enzymes and biocatalysis (towards green
chemistry).
Olivia Novac
Office of Sponsored Research
McGill University
Tel: 514-398-5887
Email: [email protected]
Reference code: ROI 05040
Opportunity: licensing or partnership