Kazunao Masubuchi

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

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 ofScCHS2 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 MIC50value of 0.27 μm. In the presence of RO-09-3143, theC. 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 cachs2Δ null mutants but not in the cachs3Δ null mutants. Thus, it appears that inC. albicans, inhibition of CaChs1p causes cell growth arrest, but simultaneous inhibition of CaChs1p and CaChs2p is lethal.

Synthesis and structure-activity relationships of novel fungal chitin synthase inhibitors.

A novel Candida albicans chitin synthase 1 (CaChs1) inhibitor, RO-41-0986 (1) was discovered by random screening. Systematic modification led to the identification of a highly potent CaChs1 inhibitor, RO-09-3024 (2), having strong antifungal activity against Candida spp. in vitro.

Synthesis and antifungal activities of novel 1,3-β-D-glucan synthase inhibitors. Part 1

Highly potent 1,3-beta-D-glucan synthase inhibitors 10, 11 and 13 have been identified by the chemical modification of the fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. D-Ornithine derivative (10) showed improved antifungal activity in the systemic candidiasis model in mice and reduced hepatotoxicity in vitro, as compared with 1.