Discovery of a new antifungal agent ASP2397 using a silkworm model of Aspergillus fumigatus infection.

Natural products are the major source of currently available drugs. However, screening natural product presents several challenges, including the time-consuming and labor-intensive steps required for the isolation of a drug from crude extracts as well as the differences between the activities of compounds in vitro and in vivo. To address these challenges, we used silkworm larvae infected with Aspergillus fumigatus to screen a natural products library for potent drugs to treat invasive aspergillosis. A rationally designed library was constructed using numerous, geographically diverse fungal species and then screened to collect extracts of microorganisms that had detectable anti-Aspergillus activity. We evaluated this library using cultures of A. fumigatus and a silkworm model system of A. fumigatus infection. With this model, we identified the novel antifungal compound ASP2397 that not only cured infected silkworm larvae but also increased the rates of survival of mice infected with A. fumigatus. These findings strongly support the utility of the silkworm screening system for the simple and rapid isolation of antibiotics from natural products libraries.

Identification of ten KB425796-A congeners from Paenibacillus sp. 530603 using an antifungal assay against Aspergillus fumigatus in combination with micafungin.

The discovery and characterization of natural congeners is one approach for understanding the relationship between chemical structure and biological function. We recently isolated the novel antifungal metabolite KB425796-A produced by the recently isolated bacterium Paenibacillus sp. 530603. On the basis of morphological changes of Aspergillus fumigatus induced by KB425796-A in combination with micafungin, we developed a highly sensitive screening method for the specific detection of KB425796-A congeners. Using this method, we isolated ten congeners of KB425796-A, named KB425796-B, -C, -D, -E, -F, -G, -H, -I, -J and -K, which exhibited diverse antifungal potencies against A. fumigatus. One of the most potent congeners, KB425796-C, had antifungal activities against several micafungin-resistant infectious fungi. KB425796-C can be a potential drug candidate for treating micafungin-resistant fungal infections.

Anti-herpes virus activity of polyether antibiotic CP-44161 in vivo.

In the previous study, we discovered a polyether antibiotic CP-44161, which was reported earlier as an anticoccidal agent, as an anti-varicella zoster virus compound. In this study, we demonstrated that CP-44161 had a very strong and broad anti-herpes virus activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. To determine the antiviral activity of CP-44161 in vivo, we examined its effect on the cutaneous HSV-2 infection model in Balb/c mice. CP-44161 showed inhibitory effect on lesion development as well as acyclovir (ACV) when the treatment was started from day 3. Meanwhile, in case the start of treatment was delayed until day 4, when ACV was no longer effective, the effectiveness of CP-44161 still remained. In this model, CP-44161 also showed inhibitory effect on the proliferation of HSV-2 DNA in dorsal root ganglia. This is the first article to report that polyether antibiotics can be effective on viral infection in vivo.

FR209602 and related compounds, novel antifungal lipopeptides from Coleophoma crateriformis no.738. I. Taxonomy, fermentation, isolation and physico-chemical properties.

Novel antifungal lipopeptides, FR209602, FR209603 and FR209604, were isolated from the fermentation broth of a fungal strain No. 738 which was identified as Coleophoma crateriformis from morphological and physiological characteristics. The antibiotics were purified by solvent extraction, HP-20, YMC-ODS and silica gel column chromatography and lyophilization. These compounds were structurally similar to FR901379 previously reported by ourselves which had a sulfate residue in the cyclic peptide portion.

FR209602 and related compounds, novel antifungal lipopeptides from coleophoma crateriformis no. 738. II. In vitro and in vivo antifungal activity.

The biological activities of the novel echinocandin-like lipopeptides, FR209602, FR209603 and FR209604, were evaluated. These compounds showed antifungal activity against Candida albicans and Aspergillus fumigatus attributed to inhibition of 1,3-beta-glucan synthesis. The minimum effective concentrations of these compounds against C. albicans and A1. fumigatus ranged from 0.02 to 0.04 microg/ml by microbroth dilution assay, and the IC50 values on C. albicans 1,3-beta-glucan synthase were 0.49, 0.64 and 0.72 microg/ml, respectively. FR209602 and FR209603 showed good efficacy by subcutaneous injection against C. albicans in a murine systemic infection model, with ED50 values of 2.0 and 1.9 mg/kg, respectively.

FR227673 and FR190293, novel antifungal lipopeptides from Chalara sp. No. 22210 and tolypocladium parasiticum No. 16616.

Novel antifungal lipopeptides, FR227673 and FR190293, were isolated from the fermentation broths of fungal strains Chalara sp. No. 22210 and Tolypocladium parasiticum No. 16616, respectively. These compounds have the same cyclic peptide nuclear structure as FR901379, with different side chains, and showed antifungal activity against Aspergillus fumigatus and Candida albicans attributed to inhibition of 1,3-beta-glucan synthesis.

FR220897 and FR220899, novel antifungal lipopeptides from Coleophoma empetri no. 14573.

Novel antifungal lipopeptides, FR220897 and FR220899, were isolated from the fermentation broth of a fungal strain No. 14573. This strain was identified as Coleophoma empetri No. 14573 from morphological and physiological characteristics. FR220897 and FR220899 showed antifungal activities against Aspergillus fumigatus and Candida albicans attributed to inhibition of 1,3-beta-glucan synthesis. Furthermore, FR220897 was effective in a murine model of systemic candidiasis.

FR207944, an antifungal antibiotic from Chaetomium sp. no. 217 I. Taxonomy, fermentation, and biological properties.

An antifungal antibiotic, FR207944, was isolated from the culture broth of a fungal strain Chaetomium sp. no. 217. FR207944 is a triterpene glucoside with antifungal activity against Aspergillus fumigatus and Candida albicans. Specifically, FR207944 exhibits in vitro and in vivo antifungal activity against A. fumigatus. The effects of FR207944 on the morphology of A. fumigatus were shown to be similar to those of FR901379, a known 1,3-beta-glucan synthase inhibitor. The MECs of FR207944 against A. fumigatus FP1305 and C. albicans FP633 in micro-broth dilution test were 0.039 and 1.6 mug/ml respectively. FR207944 showed good potency by subcutaneous injection and oral administration against A. fumigatus in a murine systemic infection model, with ED(50)s of 5.7 and 17 mg/kg respectively.

FR227244, a novel antifungal antibiotic from Myrothecium cinctum No. 002 Taxonomy, fermentation, isolation and physico-chemical properties.

A novel antifungal antibiotic, FR227244, was isolated from the culture broth of a fungal strain No. 002. The strain was identified as Myrothecium cinctum from morphological and physiological characteristics. This compound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatographies, and n-hexane precipitation. FR227244 is a white powder which melts at 210 to approximately 211 degrees C and possesses the molecular formula C38H58O11. FR227244 is a novel triterpene glycoside with antifungal activity against Aspergillus fumigatus. The effects of FR227244 on the morphology of A. fumigatus were shown to be similar to those of FR901379 which is a known 1,3-beta-glucan synthase inhibitor.