enfumafungin and Candidiasis

Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.

Topics: Administration, Oral; Animals; Antifungal Agents; beta-Glucans; Candida; Candidiasis; Disease Models, Animal; Glucosyltransferases; Glycosides; Half-Life; Mice; Microbial Sensitivity Tests; Stereoisomerism; Structure-Activity Relationship; Triazoles; Triterpenes

SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the

Topics: Administration, Oral; Antifungal Agents; Candida; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Echinocandins; Glucosyltransferases; Glycosides; Microbial Sensitivity Tests; Mutation; Triterpenes

The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.

Topics: Administration, Oral; Animals; Antifungal Agents; Aspergillus fumigatus; beta-Glucans; Candida albicans; Candidiasis; Glucosyltransferases; Glycosides; Half-Life; Mice; Microbial Sensitivity Tests; Structure-Activity Relationship; Terpenes; Triterpenes

In a screening of natural products with antifungal activity derived from endophytic fungi, we detected a potent activity in a culture belonging to the form-genus Hormonema, isolated from leaves of Juniperus communis. The compound is a new triterpene glycoside, showing an antifungal activity highly potent in vitro against Candida and Aspergillus and with moderate efficacy in an in vivo mouse model of disseminated candidiasis. The agent is especially interesting since its antifungal spectrum and its effect on morphology of Aspergillus fumigatus is comparable to that of the glucan synthase inhibitor pneumocandin B,,, the natural precursor of the clinical candidate MK-0991 (caspofungin acetate). An additional search for other Hormonema isolates producing improved titers or derivatives resulted in the isolation of two more strains recovered from the same plant host showing identical activity. The producing isolates were compared with other non-producing Hormonema strains by DNA fingerprinting and sequencing of the rDNA internal transcribed spacers. Comparison of rDNA sequences with other fungal species suggests that the producing fungus could be an undetermined Kabatina species. Kabatina is a coelomycetous genus whose members are known to produce Hormonema-like states in culture.

Topics: Animals; Antifungal Agents; Aspergillus; Candida; Candidiasis; DNA Fingerprinting; Dose-Response Relationship, Drug; Fungi; Glycosides; Juniperus; Mice; Molecular Sequence Data; Mycological Typing Techniques; Terpenes; Triterpenes