Basidiomycete metabolites attenuate virulence properties of Candida albicans in vitro

Abstract

Summary Secreted aspartic proteases (Saps) represent an important virulence factor facilitating fungal adherence. Several protease inhibitors (PIs), including HIV PIs, have been shown to reduce Candida adhesion. The aim of this study was to ascertain whether or not the recently discovered PIs Aureoquinone and Laccaridiones A and B, isolated from Basidiomycete cultures, or Bestatin, act as Sap‐inhibitors and/or inhibitors of fungal adhesion. Drug effects on candidial Sap‐production were determined by Sap‐ELISA. Control tubes, in the absence of drug, served as positive controls, while tubes excluding both drug and proteinase induction medium were used as negative controls. Aureoquinone as well as Laccaridiones A and B, but not Bestatin, significantly inhibited Candida albicans adhesion to both epithelial and endothelial cells in a dose dependent manner and also reduced Sap‐release (effects were not because of a direct interaction of the Basidiomycete metabolites with secreted Saps). Laccaridione B was consistently found to be the most effective PI tested. Interestingly, these drugs are neither fungistatic nor fungicidal at the concentrations applied. Laccaridione B may represent a promising novel type of antimycotic drug – targeting virulence factors without killing the yeast.

Production of Obionin A and Derivatives by the Sooty Blotch Fungus Microcyclospora malicola

“…The UV/Vis spectrum showed absorption maxima at 242, 298, and 468 nm and therefore indicated an extensive π-system. Proton NMR (l " Table 1) and 13 C HSQC NMR spectra revealed the presence of three aromatic and two aliphatic methines, three methylenes, one methoxy, and three aliphatic methyls; a database search with above informa-tion within the Dictionary of Natural Products on DVD identified obionin A (1) (l " Fig. 1) [8,9].…”

“…In the proton NMR spectrum, the signal of the oxygenated methylene was missing, and the three aromatic methines were shifted downfield to δ H 9.37, 7.96, and 7.57 ppm, indicating an electron-deficient heteroaromatic system. The 1 H, 13 C HMBC correlations from H-4 to C-2, C-3, C-5, C-6, and C-14, from H-8 to C-6, C-9, C-1′, and C-12, and from H-11 to C-9, C-7, C-12, and C-13 established the structure of 2 as the 10-aza-6-oxo derivative of 1. Notably, compounds 3 and 4 are formed by the addition of acetone and are thus considered as artifacts rather than genuine natural products.…”

Laccaridione C, a Bioactive Polyketide from the Fungus Montagnula sp.

“…R = OCH3 (3) R = OCH 2 CH 3 (4) R = H these bioactive pigmented polyketides also have potent protease inhibitory properties [6,[12][13][14][15], which is most likely the main mechanism of action of the bioactivity herein reported for 1.Biosynthetically, compound 1 is the intermediate stage between the C-11 dehydroxylated form of leptosphaerodione (4) and the C-11 methoxylated laccaridione A (2) or the C-11 ethoxylated laccaridione B (3).…”

Obionin B: an o-pyranonaphthoquinone decaketide from an unidentified fungus (MSX 63619) from the order Pleosporales

“…A related pair of o -pyranonaphthoquinones, the laccaridiones, were reported as promising antimycotic leads due to inhibition of Candida albicans adhesion to epithelial and endothelial cells, as well as the ability to reduce the release and inhibit the catalytic activity of secreted aspartic proteases. 12 These effects resulted in reduced virulence properties (e.g. colonization and penetration of host tissues) without being fungistatic or fungicidal.…”

“…colonization and penetration of host tissues) without being fungistatic or fungicidal. 12 However, only laccaridione B has been investigated for cytotoxicity towards human tumor cells, with IC 50 values ranging from 4.5 μM in the K-562 human erythroleukemia cell line to 34 μM in HeLa cervical carcinoma cells. 13 In comparison, obionin B ( 1 ) exhibited broad potency on the lower end of this range (Table 1).…”