ASP2397: a novel antifungal agent produced by Acremonium persicinum MF-347833

Abstract

The novel antifungal agent ASP2397 (Vical's compound ID VL-2397) is produced by the fungal strain MF-347833 that was isolated from Malaysian leaf litter and is identified here as an Acremonium species based on its morphology, physiological properties and 28S ribosomal DNA sequence. Because of its potential importance for producing novel antifungal agents, we determined the taxonomic and biologic properties of MF-347833. We show here that ASP2397 is a cyclic hexapeptide that chelates aluminum ion and is therefore similar to ferrichrome, a hydroxamate siderophore. However, ASP2397 differs structurally from licensed antifungal agents such as amphotericin B, triazoles and echinocandins. To understand the relationship between chemical structure and biological function, we isolated certain ASP2397 derivatives from the culture broth, and we further chemically converted the metal-free form to other derivatives.

The antifungal pipeline: a reality check

“…Its precise target inside the fungal cell remains uncertain, but ASP2397 localizes within fungi such as A. fumigatus , as it is taken up by the specific siderophore iron transporter 1 (Sit1) 66 . As mammalian cells do not have this transporter, it is hypothesized that the compound will have excellent selective fungal toxicity.…”

Advantages of the Silkworm As an Animal Model for Developing Novel Antimicrobial Agents

“…This finding led to the speculation that the culture broth of A. persicinum MF-347833 contained a mixture of antifungal compounds with therapeutic activity or without therapeutic activity. They next utilized the silkworm infection assay-guided purification method to identify therapeutically active antifungal compounds and successfully identified ASP2397 (Nakamura et al, 2017a,b) (Figure 4). ASP2397 has an MIC of 0.2 μg/ml against A. fumigatus FP1305 and is also effective against azole-resistant A. fumigatus (Arendrup et al, 2016), displays therapeutic activity in mice infected with A. fumigatus , and has no cytotoxicity toward mammalian cells at a concentration up to 50 μg/ml, indicating its potential as a therapeutic agent.…”

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

“…ASP2397 (Figure A), a cyclic hexapeptide chelating aluminum ion, was isolated from the culture broth of fungal strain MF‐347833 . It exhibited potent antifungal activity against Aspergillus species and there was no cytotoxic effect on mammalian cells at a high concentration (50 µg/mL).…”