Antibacterial epipolythiodioxopiperazine and unprecedented sesquiterpene from Pseudallescheria boydii, a beetle (coleoptera)-associated fungus

Abstract

Pseudallescheria boydii residing in the gut of coleopteran (Holotrichia parallela) larva produces four new epipolythiodioxopiperazine (ETP) boydines A-D (3-6) and two novel sesquiterpene boydenes A (7) and B (10), in addition to bisdethiobis(methylthio)-deacetylaranotin (1), bisdethiodi(methylthio)-deacetylapoaranotin (2), AM6898 A (8) and ovalicin (9). The structure elucidation was accomplished by a combination of spectral methods with quantum chemical calculations of optical rotations and electronic circular dichroism (ECD) spectra. Boydine B (4) was shown to be active against the clinical strains Bifidobacterium sp., Veillonella parvula, Anaerostreptococcus sp., Bacteroides vulgatus and Peptostreptococcus sp. with an MIC range of 0.2-0.8 μM, and the pharmacophore 3-hydroxy-2,4,6-trimethyl-5-oxooct-6-enoyl chain of 4 was shown to have (2R,3S,4S)-configurations. Boydene A (7) possessed an unprecedented carbon skeleton, suggesting an unusual biochemistry that allows an intramolecular Aldol addition in the fungus. Collectively, the finding may inspire the discovery of new antibacterial agents and the understanding on biosyntheses of polythiodioxopiperazine and sesquiterpene metabolites.

Fungal Metabolites Antagonists towards Plant Pests and Human Pathogens: Structure-Activity Relationship Studies

“…From the culture filtrates of the fungus Pseudallescheria boydii residing in the gut of a coleopteran ( Holotrichia parallela ) larva, four new epipolythiodioxopiperazines named boydines A–D ( 112 – 115 , Figure 8 ) were isolated together with six other known and new metabolites [ 68 ]. All the isolated fungal metabolites were assayed for in vitro antibacterial activity against pathogenic anaerobes isolated from clinical specimens.…”

“…Only boydine B ( 113 ) showed a strong inhibition against Peptostreptococcus sp., Bifidobacterium sp., Anaerostreptococcus sp., and Veillonella parvula with a MIC range of 0.2–0.8 μM. The SAR study on the cyclic dipeptides suggested that the antibacterial activity might be dependent on the combination of the acyl residue with a diketopiperazine nucleus condensed from two (2 R ,7 S ,7a S )-7-hydroxy-2-(methylthio)-2,3,7,7a-tetrahydro-1 H indole-2-carboxylic acids [ 68 ].…”

Natural products from microbes associated with insects

“…Additional insights into the dalesconol biosynthesis was gained from a characterization of minor dalesconols and biosynthetic intermediates only present in chemical extracts prepared from a large-scale fermentation. The ascomycete fungus Pseudallescheria boydii , isolated from the gut of the larvae of the beetle Holotrichia parallela , showed also a broad range of bioactive secondary metabolites including epipolythiodioxopiperazines, named boydines (e.g., boydine B, ( 37 )) [ 120 ]. Boydines significantly inhibit clinically relevant anaerobic bacterial strains (e.g., Bifidobacterium sp., Veillonella parvula , Anaerosterptococcus sp., Bacteroides vulgatus , and Peptostreptococcus sp.…”

Considerations of the chemical biology of microbial natural products provide an effective drug discovery strategy

“…The findings of other relevant investigations include: the production of new cytotoxic furanone analogues, paraconfuranones A (9)-H by a fungal strain belonging to Paraconiothyrium brasiliense isolated from the gut of the grasshopper, Acrida cinerea (Liu et al 2015); the production of a series of new epipolythiodioxopiperazines, boydines A (10)-D, and structurally novel sesquiterpenes, boydenes A and B (11) by a symbiotic fungus Pseudallescheria boydii, in the gut of the coleopteran larva of the beetle Holotrichia parallela (boydine B displayed significant inhibitory activity against clinically-relevant bacterial strains Bifidobacterium sp., Veillonella parvula, Anaerosterptococcus sp., Bacteroides vulgatus and Peptostreptococcus sp.) (Wu et al 2014); and the production of a new polyketide glycoside, bionectriol A (12) by a fungal strain belonging to Bionectra sp. associated with the fungus-growing ant (Apterostigma dentigerum) (Freinkman et al 2009).…”