Structure, bioactivity and toxicity of venturicidins A and B from Streptomyces sp. D828

Venturicidin, a promising natural macrolide antibiotic, holds significant potential for agricultural applications. However, concerns regarding its potential human health impacts due to residual in crops have persisted, while toxicological evaluations of venturicidin have been hindered by challenges in producing kilogram-scale pure compounds, which necessitating high-yield fermentation and cost-effective purification systems. Herein, we isolated a wild-type strain, Streptomyces species D828, which archived remarkable yields of venturicidin A (930 mg/L) and B (460 mg/L) when cultured in PG₃ medium. Mechanistically, venturicidin exerts potent antifungal activity against the rice blast pathogen Pyricularia oryzae through the specific inhibition of fungal mitochondrial F₁F₀-ATPase. In greenhouse trials, application of a 50 mg/L venturicidin reduced rice blast incidence by 92 %. Acute toxicity assessments classified the venturicidin mixture as low-toxic with oral LD₅₀ > 2000 mg/kg·bw, dermal LD₅₀ > 2000 mg/kg·bw, inhalation LC₅₀ > 5000 mg/m³·bw and aquatic LC₅₀ > 10 mg/L, aligning with OECD/GHS criteria. Furthermore, histological analyses of zebrafish organs using hematoxylin-eosin-stained paraffin sections and transmission electron microscopy revealed no significant structural alterations following 96-h exposure to venturicidin. Notably, our strain has the highest yields of venturicidin to date, positioning it as a viable platform for industrial-scale production. Additionally, we predicted Pyricularia oryzae ATP synthase subunit C structure (venturicidin's target) and identified interaction sites. Generally, the dual merits of target-specific antifungal potency (IC₉₀ = 0.115 mg/L) and minimal toxicity establish venturicidin as a promising candidate for next-generation fungicides.