Bioprospecting Endophytic Fungi for Antiplasmodial Metabolites Through Mechanistic Pathways, Cultivation Challenges and Drug Development Prospect

Fungal endophytes are increasingly recognized as reservoirs of diverse biologically active secondary metabolites with antimalarial potential. This review focuses on isolation, cultivation, bioactivity, and translational relevance in antimalarial properties of fungal endophyte. Careful plant selection, effective surface sterilization, and appropriate culture conditions remain critical for the recovery of endophytic fungi. However, challenges in reproducibility and in vitro cultivation persist. Proper morphological and molecular identification of fungi provides insights into the diversity of the endophytic fungal community and their metabolic bioactivity. In vitro antiplasmodial assays have shown prospective inhibitory activity of endophytic extracts against Plasmodium falciparum with very low IC50 values. Similar to those reported in higher plants, metabolites in endophytes consist of alkaloids, non-ribosomal peptides, polyketides, quinones, terpenoids and xanthones. These phytochemicals have been implicated in heme detoxification, disruption of redox homeostasis, or interruption of key parasite biosynthetic pathways. Heme detoxification is a process by which Plasmodium spp degrades hemoglobin and releasing toxic free heme (ferriprotoporphyrin IX). Promoting in vivo investigations in non-human malaria models aid the bioprospection of these metabolites and further gain insight to toxicity evaluations and mechanism of action. The main challenges in bioprospecting endophytes include inadequate sample preparation, metabolite variability, and incorrect nomenclature of isolated compounds, incorrect nomenclature of the isolated chemical candidates. Efforts should be geared toward prioritizing standardization of screening, integration of multi-omics and genome mining and strategies to improve secondary metabolite yields of secondary metabolites in discovering potent antimalarial candidates in an era of drug resistance upsurge.