Cryptococcus neoformans Ilv2p confers resistance to sulfometuron methyl and is required for survival at 37 °C and in vivo

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Abstract
Acetolactate synthase catalyses the first common step in isoleucine and valine biosynthesis and is the target of several classes of inhibitors. TheCryptococcus neoformans ILV2gene, encoding acetolactate synthase, was identified by complementation of aSaccharomyces cerevisiae ilv2mutant.C. neoformansis highly resistant to the commercially available acetolactate synthase inhibitor, sulfometuron methyl (SM). Expression ofC. neoformans ILV2inS. cerevisiaeconferred SM resistance, indicating that the SM resistance ofC. neoformansis due, at least in part, toC. neoformansIlv2p. TheC. neoformans ILV2gene was disrupted. Theilv2mutants were auxotrophic for isoleucine and valine and the auxotrophy was satisfied by these amino acids only when proline, and not ammonium, was the nitrogen source, indicating nitrogen regulation of amino acid transport.ilv2mutants rapidly lost viability at 37 °C and when starved for isoleucine and valine. Consistent with these phenotypes, anilv2mutant was avirulent and unable to survive in mice. BecauseC. neoformansIlv2p is required for virulence and survivalin vivo, inhibitors of branched-chain amino acid biosynthesis may make valuable antifungal agents.