Abstract
Bengazoles A–G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole―a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase―showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.
Highlights
The tropical sponge, Jaspis cf. coriacea, is the original source of two classes of unrelated natural products: bengazoles and bengamides, (Figure 1) first reported by Crews et al [1]
The precise molecular mechanism of action (MOA) of the bengazoles has not been determined, but we have shown that the antifungal activity of 2a was suppressed in the presence of exogenous ergosterol (3) in a concentration-dependent manner [20], reminiscent of the MOA of polyene antifungal agents
Analysis of saponified cultures of C. albicans treated with clotrimazole (5) showed the appearance of eburicol (7)—a shunt metabolite sterol biosynthesis as expected—whereas cultures treated with bengazoles (2) did not
Summary
The tropical sponge, Jaspis cf. coriacea, is the original source of two classes of unrelated natural products: bengazoles and bengamides, (Figure 1) first reported by Crews et al [1]. A (1a) [2,3] and B (1b) and related analogs are potent nanomolar inhibitors of cancer cell growth, with selective in vitro activity in the NCI 60 cell line panel [4]. Compound 1a reduced MDA-MB-435 breast carcinoma in an in vivo rat zenograft model [4]. The unique cytotoxicity of bengamides has been attributed to the inhibition of methionine aminopeptidases [5,6]. A synthetic analog of 1a, LAF-389 [7], was advanced to phase I clinical trials before discontinuation of the study due to intolerable toxicity [8].
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