The Cyanobacterial Oxadiazine Nocuolin A Shows Broad-Spectrum Toxicity Against Protozoans and the Nematode C. elegans

Cyanobacteria, known to be rich sources of valuable natural products (NPs) with relevant biological properties, are a unique subject to study the interplay between chemistry and ecology. Cultivation of cyanobacteria as isolated strains may only reveal a small fraction of their NPs. In contrast, investigating microbial interactions from an ecological perspective is a particularly fruitful approach to unveil both new chemistry and bioactivity. Cyanobacteria and amoebae are known to co-exist in diverse environments, but the interaction between these organisms has been poorly investigated. Defense strategies against grazer organisms may rely on morphological changes including biofilm formation or increased motility; however, secretion of toxic metabolites seems to be more effective on this regard. Among the most structurally unique cyanobacterial secondary metabolites is nocuolin A, an 1,2,3-oxadiazine metabolite isolated from the cyanobacterial strain Nodularia sp. LEGE 06071 that exhibits potent anti-proliferative activity against several human cancer lines, associated with impairment of mitochondrial oxidative phosphorylation. In this work, we show that nocuolin A is toxic against two well-known model amoebae, Acanthamoeba and Dictyostelium, leading to amoebae encystation and decrease in viability. In addition, in lawn grazing assays, we observed that Nodularia sp. LEGE 06071, the producer strain of nocuolin A, was not grazed by amoeba, while a related strain, which does not produce detectable levels of nocuolin A, was. These results support the possible involvement of nocuolin A as a chemical mediator during the interaction between these organisms. Furthermore, we show that this cyanobacterial metabolite also exhibits potent toxicity against other protozoan organisms and a free-living nematode, making it an interesting broad-spectrum scaffold for the development of antiprotozoal or anti-helminthic drugs.