Professor
Department of Biochemistry

Development of antimicrobials, antibiotic resistance, crystallography

Francesco Bellini Life Sciences Building
3649 Promenade Sir William Osler
Office: Room 466; Lab: Room 468/470
Montreal, QC H3G 0B1
Tel: 514-398-8795; Lab: 514-398-8781/ 2177
Fax: 514-398-3387
Email
Berghuis Lab

Canada Research Chair in Structural Biology

In the news:
Turning drug design on its head McGill Reporter, May 8, 2003 - Vol. 35 No. 15)
Antibiotic Resistance and Target Mimicry (NSLS Science Highlights, October 9, 2002)

Research Interests

Various research programs are being pursued in the Berghuis lab. However, all programs share a common theme in that they use structural biological approaches to examine interactions between enzymes and small molecules (e.g. substrates, cofactors, inhibitors). The principal technique used for these studies is X-ray crystallography, complemented with nuclear magnetic resonance spectroscopy, enzymology and computational chemistry tools. Furthermore, for many of these programs, efforts are ongoing to exploit the three-dimensional structural information for drug development using a combination of high-throughput screening and structure-based drug design approaches. Below two programs are highlighted.

A. Structural Studies of Antibiotic Resistance Mechanisms
Over the past few decades there has been a dramatic rise in antibiotic resistance, and the situation has now culminated in bacteria that are effectively resistant to all clinically used antibiotics. The research is aimed at dissecting the structural basis for clinical resistance against various antibiotics. Specifically aminoglycoside and streptogramin resistance mechanisms are examined. These antibiotics have lost their potency due to bacterial enzymes that either covalently modify or cleave the drugs. For example, we have determined the detailed mechanism by which aminoglycoside kinases confer resistance to drugs such as gentamicin and kanamycin, and we are currently exploiting this knowledge towards the development of adjuvants.

B. Structural Studies of the Fungal Amino Acid Pathways
Fungal infections are a rising concern in the health care sector since pathogenic fungi have become an important cause of mortality for individuals with diminished immune systems. The concern for fungal infections is amplified by the fact that there are a very limited number of antimycotic drugs available and resistance against most commonly used antifungal agents has been observed. To assist in the drug discovery process for novel antimycotic agents, we are pursuing structural studies of fungal enzymes that are involved in the synthesis of essential amino acids. These synthetic pathways are absent in mammals, and as such pose an excellent target for the development of antimicrobial drugs. For example, we have determined the structure of the fungal enzyme homoserine dehydrogenase in complex with a drug lead that is able to clear systemic candidiasis in a mouse model.

Selected Publications

Mirza IA, Nazi I, Korczynska M, Wright GD, Berghuis AM (2005) Crystal Structure of Homoserine Transacetylase from Haemophilus influenzae Reveals a New Family of alpha/beta-Hydrolases. Biochem. J. 44:15768-15773.

Jacques SL, Mirza IA, Ejim L, Koteva K, Hughes DW, Green K, Kinach R, Honek JF, Lai HK, Berghuis AM, Wright GD (2003) Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase. Chem Biol 10:989-995.

Burk DL, Berghuis AM (2002) Protein kinase inhibitors and antibiotic resistance. Pharmacol. Ther. 93:283-292.

Fong DH, Berghuis AM (2002) Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry. EMBO J. 15:2323-2331.

DeLaBarre B, Thompson PR, Wright GD, Berghuis AM (2000) Crystal structures of homoserine dehydrogenase suggest a novel catalytic mechanism for oxidoreductases. Nat Struct Biol 7:238-244.

Wybenga-Groot LE, Draker K, Wright GD, Berghuis AM (1999) Crystal structure of an aminoglycoside 6'-N-acetyltransferase: defining the GCN5-related N-acetyltransferase superfamily fold. Structure Fold Des 7:497-507.

Hon WC, McKay GA, Thompson PR, Sweet RM, Yang DS, Wright GD, Berghuis AM (1997) Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 13:887-895.

Publications (complete list) - Albert Berghuis