Appraisal of Fungus-Derived Xanthoquinodins as Broad-Spectrum Anti-Infectives Targeting Phylogenetically Diverse Human Pathogens

Xanthoquinodinsmake up a distinctive class of xanthone-anthraquinoneheterodimers reported as secondary metabolites from several fungalspecies. Through a collaborative multi-institutional screening program,a fungal extract prepared from a Trichocladium sp.was identified that exhibited strong inhibitory effects against severalhuman pathogens (Mycoplasma genitalium, Plasmodiumfalciparum, Cryptosporidium parvum, and Trichomonas vaginalis). This report focuses on one of theunique samples that exhibited a desirable combination of biologicaleffects: namely, it inhibited all four test pathogens and demonstratedlow levels of toxicity toward HepG2 (human liver) cells. Fractionationand purification of the bioactive components and their congeners ledto the identification of six new compounds [xanthoquinodins NPDG A1-A5(1-5) and B1 (6)] aswell as several previously reported natural products (7-14). The chemical structures of 1-14 were determined based on interpretation oftheir 1D and 2D NMR, HRESIMS, and electronic circular dichroism (ECD)data. Biological testing of the purified metabolites revealed thatthey possessed widely varying levels of inhibitory activity againsta panel of human pathogens. Xanthoquinodins A1 (7) andA2 (8) exhibited the most promising broad-spectrum inhibitoryeffects against M. genitalium (EC50 values:0.13 and 0.12 mu M, respectively), C. parvum (EC50 values: 5.2 and 3.5 mu M, respectively), T.vaginalis (EC50 values: 3.9 and 6.8 mu M,respectively), and P. falciparum (EC50 values: 0.29 and 0.50 mu M, respectively) with no cytotoxicitydetected at the highest concentration tested (HepG2 EC50 > 25 mu M).

Automated summary

Xanthoquinodins are a unique class of compounds found in several fungal species, and they have been reported as secondary metabolites. A fungal extract from Trichocladium sp. was found to have strong inhibitory effects against several human pathogens. Six new compounds and several previously reported natural products were identified through purification and analysis. Among them, Xanthoquinodins A1 and A2 showed the most promising broad-spectrum inhibitory effects against multiple human pathogens.