The Discovery of Actinospene, a New Polyene Macrolide with Broad Activity against Plant Fungal Pathogens and Pathogenic Yeasts

Abstract

Phytopathogenic fungi infect crops, presenting a worldwide threat to agriculture. Polyene macrolides are one of the most effective antifungal agents applied in human therapy and crop protection. In this study, we found a cryptic polyene biosynthetic gene cluster in Actinokineospora spheciospongiae by genome mining. Then, this gene cluster was activated via varying fermentation conditions, leading to the discovery of new polyene actinospene (1), which was subsequently isolated and its structure determined through spectroscopic techniques including UV, HR-MS, and NMR. The absolute configuration was confirmed by comparing the calculated and experimental electronic circular dichroism (ECD) spectra. Unlike known polyene macrolides, actinospene (1) demonstrated more versatile post-assembling decorations including two epoxide groups and an unusual isobutenyl side chain. In bioassays, actinospene (1) showed a broad spectrum of antifungal activity against several plant fungal pathogens as well as pathogenic yeasts with minimum inhibitory concentrations ranging between 2 and 10 μg/mL.

New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining

“…"New" structures result from use of a wider range of polyketide starter and extender units, from formation of linear polyene-polyol analogues, and from additional late steps, such as glycosylation and cytochrome P450-catalyzed modifications. NPP A1, Pseudonocardia P1 mannosyl-nystatin, selvamicin, meijiemycin, and kineosporicin/actinospene have been purified and characterized relatively recently [21,67,69,81,82,108]. Genome mining indicates that even more new polyenes are encoded by silent clusters.…”

“…Actinokineospora spheciospongiae DSM45935 synthesizes a methyltetraene that is glycosylated with D-perosamine, contains two epoxide groups, and is also unusual in that it is hydroxylated at C10 (Figure 14). This tetraene has been characterized independently by two groups and named kineosporicin [21] and actinospene [69]. The Actino.…”

“…Actinospene was active against yeasts and filamentous fungi and had MICs comparable to those of pimaricin (2 to 10 µg/mL). The diepoxide and the extra C10 hydroxylation apparently do not increase antifungal activity but could have other positive effects on other pharmacological properties [21,69].…”

Marine natural products

“…652 Investigation of engineered variants of aconotoxin LvIB identied the inuence of residues Gln141, Asn184 and Lys186 on a7 nAChR species selectivity. 653 Xylenelinked cysteine [2,4] modied analogues of a-conotoxin TxIB have enhanced serum stability and show selectivity towards a6/ a3b2b3 nAChR's 654 while an alkyne variant, replacing cysteine [1,3], of a-conotoxin Vc1.1 failed to inhibit a7 and ha9a10 nAChR's but was a GABA B R selective agonist and also reversed mechanical allodynia in vivo. 655 a-Conotoxins promote the proliferation of C6 glioma cells in vitro.…”

“…This molecule showed a broad spectrum of antifungal activity against several plant fungal pathogens as well as pathogenic yeasts with MIC values ranging from 2–10 μg mL −1 . 3 New antibacterial tetronate-based polyketide derivatives, nomimicins A–D 2–5 , were identified from a fermentation culture of an Actinomadura strain, 4 whilst chemical examination of an Aquimarina sp. bioactive broth yielded caprolactin C 6 , which, along with its enantiomer ( ent -caprolactin C), were synthesised.…”