RESUMO
Novel open-chain merocytochalasans, perochalasins A-C (1-3), containing an unusual N-O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived Peroneutypa sp. M16 fungus, along with cytochalasin Z27 (4), cytochalasin Z28 (5), [12]-cytochalasin (6), and phenochalasin B (7). The structures of compounds 1-3 were established by analysis of the spectroscopic data. Full genome sequencing of Peroneutypa sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B (7) into 1-3, based on isotope-labeled hydroxylamine (15NH2OH and ND2OD) feeding studies in vivo and in vitro. In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z27 (4) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive Plasmodium falciparum 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).
Assuntos
Citocalasinas , Citocalasinas/farmacologia , Citocalasinas/química , Citocalasinas/biossíntese , Citocalasinas/isolamento & purificação , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/farmacologia , Antimaláricos/química , Família MultigênicaRESUMO
Microorganisms interact chemically in natural environments; however, the compounds and mechanisms involved in this phenomenon are still poorly understood. Using the cocultivation approach, changes in metabolic profiles due to interactions between endophytic fungal and actinobacterial strains isolated from the plant Lychnophora ericoides (Asteraceae) were assessed. The production of the cytotoxic compound cytochalasin H by the fungus Phomopsis sp. FLe6 was remarkably inhibited in solid and liquid co-cultures with the actinobacteria Streptomyces albospinus RLe7. This was a consequence of the fungal growth inhibition caused by antifungal compounds produced by S. albospinus RLe7, including amphotericin B. Cytochalasin H is not toxic to S. albospinus RLe7, suggesting that this microorganism does not require a defense mechanism to prevent the potentially harmful effects of such fungal compound. By exhibiting various competitive phenotypes, these microbes can control each other's growth when sharing an environment.