Endophytic Aspergillus glaucus as a novel epothilone B producer: Antiproliferative activity and in silico analysis

Abstract

Epothilones are natural macrolides that represent hybrid secondary metabolites derived from polyketide and nonribosomal peptide biosynthetic pathways, characterized by epoxide, thiazole, and ketone moieties (Gerth et al. 1996 ). They were initially isolated from the myxobacterium Sorangium cellulosum and exhibited potent anticancer activity against a wide range of solid tumors (Mühlradt and Sasse 1997 ). The anticancer efficacy of epothilones is primarily attributed to their high binding affinity for β-tubulin, which stabilizes microtubules and inhibits their depolymerization, thereby arresting cell division at the G2/M phase (Mühlradt and Sasse 1997 ). Epothilones and Taxol share a common molecular target, β-tubulin, interfering with its function during the cellular mitotic division (Cheng et al. 2008 ; Villegas et al. 2023 ). Nevertheless, epothilones possess several favorable biological properties compared with Taxol, including higher aqueous solubility, lower molecular weight, and reduced binding energy toward tubulin (Lee and Swain 2008 ). These physicochemical advantages contribute to the superior anticancer activity of epothilones, particularly against drug-resistant tumor phenotypes (Gerth et al. 1996 ). Microtubule-targeting agents are generally classified into two major categories: microtubule-stabilizing agents, such as epothilones and Taxol, and microtubule-destabilizing agents, including vinca alkaloids and colchicine (Pham et al. 2023 ; Ye et al. 2019 ; Zhao et al. 2011 ). Epothilones and Taxol bind to the same recognition site on microtubules, suppressing tumor cell proliferation by inducing microtubule polymerization and stabilization (Chandra 2012 ; Sohn and Okos 1998 ). Although epothilones are naturally produced by S. cellulosum , the extremely slow growth rate of this bacterium, together with low epothilone yields, significantly limits its feasibility as a commercial production platform and constrains large-scale production and clinical implementation (Penazzi et al. 2016 ; Ye et al. 2019 ). Recently, fungal species such as Aspergillus fumigatus (El-Sayed et al. 2021b , 2025 ) and Aspergillus niger (Refaat et al. 2024 ) have been reported to produce epothilone B with a chemical structure identical to that of the authentic compound originally isolated from S. cellulosum . The overall epothilone yield obtained from A. fumigatus and A. niger was approximately 6.2-fold higher than that reported for Burkholderia species (Li et al. 2013 ). Although the feasibility of fungal culture manipulation for epothilone production is promising, a progressive decline in epothilone productivity during fungal storage and repeated subculturing remains a major challenge. Accordingly, screening for novel fungal isolates exhibiting enhanced epothilone productivity and long-term biosynthetic stability has become a primary research objective. In this context, endophytic fungi inhabiting medicinal plants with established ethnopharmacological relevance are considered promising sources of structurally diverse and biologically active secondary metabolites (El-Sayed et al. 2017 , 2022 ). Members of the family Arecaceae are well recognized for their ethnopharmacological importance and rich phytochemical diversity (Shukla and Dubey 2022 ). The palm tree Latania lontaroides is a representative species of the Arecaceae family; however, limited studies have investigated its bioactive metabolites or the diversity and biosynthetic potential of its associated endophytic fungi. Accordingly, the present study aimed to isolate and characterize endophytic fungi from L. lontaroides , evaluate their epothilone-producing capacity and biosynthetic stability, and elucidate the chemical identity and biological activity of the produced epothilone.