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J. Biol. Chem., Vol. 275, Issue 42, 32901-32905, October 20, 2000

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Identification of a Novel Inhibitor Specific to the Fungal Chitin Synthase
INHIBITION OF CHITIN SYNTHASE 1 ARRESTS THE CELL GROWTH, BUT INHIBITION OF CHITIN SYNTHASE 1 AND 2 IS LETHAL IN THE PATHOGENIC FUNGUS CANDIDA ALBICANS^*

Masayuki Sudoh, Toshikazu Yamazaki, Kazunao Masubuchi^§, Mikio Taniguchi^§, Nobuo Shimma^§, Mikio Arisawa, and Hisafumi Yamada-Okabe^¶

From the  Department of Mycology and Oncology and the ^§ Department of Chemistry, Nippon Roche Research Center, Kanagawa 247-8530, Japan

As in Saccharomyces cerevisiae, the pathogenic fungus Candida albicans harbors three chitin synthases called CaChs1p, CaChs2p, and CaChs3p, which are structurally and functionally analogous to the S. cerevisiae ScChs2p, ScChs1p, and ScChs3p, respectively. In S. cerevisiae, ScCHS1, ScCHS2, and ScCHS3 are all non-essential genes; only the simultaneous disruption of ScCHS2 and ScCHS3 is lethal. The fact that a null mutation of the CaCHS1 is impossible, however, implies that CaCHS1 is required for the viability of C. albicans. To gain more insight into the physiological importance of CaCHS1, we identified and characterized a novel inhibitor that was highly specific to CaChs1p. RO-09-3143 inhibited CaChs1p with a K_i value of 0.55 nM in a manner that was non-competitive to the substrate UDP-N-acetylglucosamine. RO-09-3143 also hampered the growth of the C. albicans cells with an MIC₅₀ value of 0.27 µM. In the presence of RO-09-3143, the C. albicans cells failed to form septa and displayed an aberrant morphology, confirming the involvement of the C. albicans Chs1p in septum formation. Although the effect of RO-09-3143 on the wild-type C. albicans was fungistatic, it caused cell death in the cachs2 null mutants but not in the cachs3 null mutants. Thus, it appears that in C. albicans, inhibition of CaChs1p causes cell growth arrest, but simultaneous inhibition of CaChs1p and CaChs2p is lethal.

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