Oxalactam A, a Novel Macrolactam with Potent Anti- Rhizoctonia solani Activity from the Endophytic Fungus Penicillium oxalicum

Abstract

A novel macrolactam named oxalactam A (1), three known dipeptides (2-4) as well as other known alkaloids (5-7) were obtained from the endophytic fungus Penicillium oxalicum, which was derived from the tuber of Icacina trichantha (Icacinaceae). All chemical structures were established based on spectroscopic data, chemical methods, ECD calculations, and ¹³C-DP4+ analysis. Among them, oxalactam A (1) is a 16-membered polyenic macrolactam bearing a new skeleton of 2,9-dimethyl-azacyclohexadecane core and exhibited potent anti-Rhizoctonia solani activity with a MIC value of 10 μg/mL in vitro. The plausible biosynthetic pathway of 1 was also proposed via the alanyl protecting mechanism. Notably, three dipeptides (2-4) were first identified from the endophytic fungus P. oxalicum and the NMR data of cyclo(L-Trp-L-Glu) (2) was reported for the first time. In addition, the binding interactions between compound 1 and the sterol 14α-demethylase enzyme (CYP51) were studied by molecular docking and dynamics technologies, and the results revealed that the 16-membered polyenic macrolactam could be a promising CYP51 inhibitor to develop as a new anti-Rhizoctonia solani fungicide.

Keywords: Penicillium oxalicum; anti-Rhizoctonia solani; macrolactam; molecular docking; molecular dynamics; oxalactam A.

Figure 1

Chemical structures of compounds 1–7.

Figure 2

Key ¹H–¹H COSY and HMBC correlations of 1.

Figure 3

Linear correlation plots of calculated-experimental ¹³C NMR chemical shift values for (3R*,15S*,16S*)–1, (3S*,15S*,16S*)–1, (3S*,15R*,16S*)–1, and (3R*,15R*,16S*)–1.

Figure 4

Experimental ECD for 1 and calculated ECD spectra for 1 and its enantiomer.

Figure 5

Proposed biosynthesis pathway of 1.

Figure 6

2D and 3D images of oxalactam A (1) with the target protein CYP51 (Pink dotted lines: Pi-Alkyl interactions, light green dotted lines: Van Der Waals interactions, deep green dotted lines: Conventional hydrogen bond).

Figure 7

2D and 3D images of hexaconazole with the target protein CYP51 (Orange dotted lines: Pi-Anion interactions, pink dotted lines: Pi-Alkyl interactions, purple dotted lines: Pi-Sigma interactions).

Figure 8

Molecular dynamics trajectory analysis of CYP51–1 and CYP51–hexaconazole complexes, including the RMSD, RMSF, and the total energy.