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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 <jats:italic>Nodularia<\/jats:italic> 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, <jats:italic>Acanthamoeba<\/jats:italic> and <jats:italic>Dictyostelium<\/jats:italic>, leading to amoebae encystation and decrease in viability. In addition, in lawn grazing assays, we observed that <jats:italic>Nodularia<\/jats:italic> 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.<\/jats:p>","DOI":"10.1007\/s00248-025-02507-2","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T05:04:27Z","timestamp":1741064667000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Cyanobacterial Oxadiazine Nocuolin A Shows Broad-Spectrum Toxicity Against Protozoans and the Nematode C. elegans"],"prefix":"10.1007","volume":"88","author":[{"given":"Ana R.","family":"Vieira","sequence":"first","affiliation":[]},{"given":"Francisco","family":"Camacho","sequence":"additional","affiliation":[]},{"given":"Maria L.","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Sara","family":"Luelmo","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Santar\u00e9m","sequence":"additional","affiliation":[]},{"given":"Anabela","family":"Cordeiro-da-Silva","sequence":"additional","affiliation":[]},{"given":"Pedro N.","family":"Le\u00e3o","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"2507_CR1","doi-asserted-by":"publisher","unstructured":"Abt K, Castelo-Branco R , Le\u00e3o PN (2021) Biosynthesis of chlorinated lactylates in Sphaerospermopsis sp. 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