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Antimicrob. Agents Chemother. doi:10.1128/AAC.01400-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Role of Homoserine Transacetylase as a New Target for Antifungal Agents

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

^* To whom correspondence should be addressed. Email: wrightge{at}mcmaster.ca.

	Abstract

Microbial amino acid biosynthesis is a proven yet underexploited target of antibiotics. The biosynthesis of Methionine (Met) 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_Cn by complementation of an Escherichia coli metA mutant that lacks the gene encoding homoserine transsuccinylase (HTS). We cloned, expressed, and purified HTA_Cn and determined its steady state kinetic parameters for the acetylation of L-Hse by acetylCoA. 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 1000 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 drugable target for new antifungal agent design.

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