HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans

The antifungal properties of 515 synthetic and semi-synthetic protoberberin es were investigated. HWY-289 was chosen for further study because it exhib ited the most significant anti-Candida activity (MICs were 1.56 mg/L for Ca ndida albicans and Candida krusei; 6.25 mg/L for Candida guilliermondii) bu t did not demonstrate toxicity in rats. HWY-289 inhibited the incorporation of L-[methyl-C-14]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC50 20 muM). However, HWY-289 (100 muM) had no effect on mam malian cholesterol biosynthesis in rat microsomes while miconazole (100 muM ) was a potent inhibitor of cholesterol biosynthesis under identical assay conditions. A second major target site for HWY-289 was identified that invo lves cell wall biosynthesis in C. albicans, HWY-289 was a potent inhibitor of the chitin synthase isozymes CaCHS1 and CaCHS2, with IC50 values of 22 m uM for each enzyme. The effect was highly specific in that HWY-289 had no s ignificant effect on C, albicans CaCHS3 (IC50 > 200 muM). Thus, HWY-289 com pared favourably with well-established antifungal agents as an inhibitor of the growth of Candida species in vitro, and may have considerable potentia l as a new class of antifungal agent that lacks toxic side effects in the h uman host.