Substrate-dependent metabolites from mangrove-derived Aspergillus ochraceus PLP1F21 exhibit antibacterial and wound healing activities.

Mangrove-derived Aspergillus sp. represents a promising source of bioactive secondary metabolites with potential therapeutic applications. The One Strain-Many Compounds (OSMAC) approach was employed to modulate metabolite production of Aspergillus ochraceus PLP1F21 from Pesawaran, Indonesia, using three agro-industrial waste substrates: shrimp shell (PLP1-SS), rice medium (PLP1-RM), and palm mesocarp fibre (PLP1-PW). Ethyl acetate extracts were evaluated for antibacterial activity against clinically isolated multidrug-resistant (MDR) Staphylococcus aureus and Pseudomonas aeruginosa, and for wound healing efficacy in MDR-infected murine dorsal incision models. PLP1-SS exhibited direct antibacterial activity against both pathogens (minimum inhibitory concentration 250 μg/mL) and promoted superior wound closure in the P. aeruginosa model (0.59 ± 0.03 cm2 on Day 7); liquid chromatography-high resolution mass spectrometry profiling putatively attributed this dual activity to notoamide-class prenylated indole alkaloids. PLP1-PW, despite negligible antibacterial activity, promoted wound contraction in the S. aureus model (0.85 ± 0.03 cm2) with a metabolite profile enriched in terpenoids and polyketides, suggesting host-directed repair mechanisms. PLP1-RM similarly enhanced wound closure (0.32 ± 0.02 cm2), although its chemical basis remains uncharacterised. Histopathological evaluation revealed selective macrophage infiltration without neutrophilic or lymphocytic elevation in the S. aureus model, indicative of a controlled pro-repair immune response, while no significant immune modulation was detected in the P. aeruginosa model. These findings demonstrate that OSMAC cultivation on agro-industrial waste substrates generates metabolically distinct extracts with substrate-dependent activities, highlighting PLP1-SS and PLP1-PW as promising candidates for infected wound management.