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Antimicrobial Agents and Chemotherapy, May 2007, p. 1731-1736, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01400-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Homoserine Transacetylase as a New Target for Antifungal Agents{triangledown}

Ishac Nazi,1 Adam Scott,1 Anita Sham,2 Laura Rossi,1 Peter R. Williamson,3 James W. Kronstad,2 and Gerard D. Wright1*

Antimicrobial Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, Ontario, Canada L8N 3Z5,1 The Michael Smith Laboratories, The University of British Columbia, 2185 East Mall, Vancouver, British Columbia, Canada V6T 1Z4,2 Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois3

Received 8 November 2006/ Returned for modification 21 January 2007/ Accepted 30 January 2007

Microbial amino acid biosynthesis is a proven yet underexploited target of antibiotics. The biosynthesis of methionine in particular has been shown to be susceptible to small-molecule inhibition in fungi. The first committed step in Met biosynthesis is the acylation of homoserine (Hse) by the enzyme homoserine transacetylase (HTA). We have identified the MET2 gene of Cryptococcus neoformans H99 that encodes HTA (CnHTA) by complementation of an Escherichia coli metA mutant that lacks the gene encoding homoserine transsuccinylase (HTS). We cloned, expressed, and purified CnHTA and determined its steady-state kinetic parameters for the acetylation of L-Hse by acetyl coenzyme A. We next constructed a MET2 mutant in C. neoformans H99 and tested its growth behavior in Met-deficient media, confirming the expected Met auxotrophy. Furthermore, we used this mutant in a mouse inhalation model of infection and determined that MET2 is required for virulence. This makes fungal HTA a viable target for new antibiotic discovery. We screened a 1,000-compound library of small molecules for HTA inhibitors and report the identification of the first inhibitor of fungal HTA. This work validates HTA as an attractive drug-susceptible target for new antifungal agent design.

* Corresponding author. Mailing address: Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W, Hamilton, Ontario, Canada L8N 3Z5. Phone: (905) 525-9140, ext. 22454. Fax: (905) 522-9033. E-mail: wrightge{at}mcmaster.ca

{triangledown} Published ahead of print on 12 March 2007.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1731-1736, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01400-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kingsbury, J. M., McCusker, J. H. (2008). Threonine biosynthetic genes are essential in Cryptococcus neoformans. Microbiology 154: 2767-2775 [Abstract] [Full Text]  


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