Genome-guided discovery of coublibactins from Nocardia coubleae and their gallium complexes with potent antileukemic activity

Abstract

The pursuit of highly effective and selective anticancer drugs remains a critical challenge. Metal-based complexes, particularly gallium-containing compounds, offer promising therapeutic avenues due to their unique mechanisms of action. To identify novel scaffolds for such complexes, we performed a comprehensive genomic analysis of Nocardia species, revealing the prevalence of siderophore biosynthetic gene clusters, including the highly conserved nocobactin NA-like clusters. From N. coubleae DSM 44960, we isolated three new siderophores, coublibactins A-C (1-3), along with eight congeners (4-11) with known planar structures, all characterized by exceptional iron-binding affinity. Subsequent gallium substitution yielded gallium complexes (Ga-1-11). Among these, Ga-6 exhibited significant anticancer activity against human acute promyelocytic leukemia NB4 cells with IC₅₀ value of 1.35 μM. Pharmacological studies showed that Ga-6 induces cell cycle arrest and apoptosis in NB4 cells. Our findings revealed microbial siderophores as promising scaffolds for the design of next-generation metal-based anticancer therapeutics, particularly gallium-based agents.

Keywords: Anticancer agents; Galium-based complexes; Nocardia; Siderophores.