Abstract
New fungal SMs (SMs) have been successfully described to be produced by means of in vitro-simulated microbial community interactions. Co-culturing of fungi has proved to be an efficient way to induce cell–cell interactions that can promote the activation of cryptic pathways, frequently silent when the strains are grown in laboratory conditions. Filamentous fungi represent one of the most diverse microbial groups known to produce bioactive natural products. Triggering the production of novel antifungal compounds in fungi could respond to the current needs to fight health compromising pathogens and provide new therapeutic solutions. In this study, we have selected the fungus Botrytis cinerea as a model to establish microbial interactions with a large set of fungal strains related to ecosystems where they can coexist with this phytopathogen, and to generate a collection of extracts, obtained from their antagonic microbial interactions and potentially containing new bioactive compounds. The antifungal specificity of the extracts containing compounds induced after B. cinerea interaction was determined against two human fungal pathogens (Candida albicans and Aspergillus fumigatus) and three phytopathogens (Colletotrichum acutatum, Fusarium proliferatum, and Magnaporthe grisea). In addition, their cytotoxicity was also evaluated against the human hepatocellular carcinoma cell line (HepG2). We have identified by LC-MS the production of a wide variety of known compounds induced from these fungal interactions, as well as novel molecules that support the potential of this approach to generate new chemical diversity and possible new therapeutic agents.
Highlights
The continued emergence of new resistances to the existing drugs, even for the most common organisms, is challenging the future use of the limited current therapies
Once identified most of the known metabolites produced by B. cinerea, and those produced by the other fungal strains independently of the interaction, we studied the molecules only present in the co-culturing extracts that could correspond to induced compounds produced by each of the other fungi in the microbial interaction
As response to the attack of the co-culturing strain, we confirmed that B. cinerea produced some of these natural products that were included among the group of molecules that were detected in the LC-HRMS chemical profiles of the active extracts
Summary
The continued emergence of new resistances to the existing drugs, even for the most common organisms, is challenging the future use of the limited current therapies. Invasive fungal infections are an important cause of morbidity and mortality, especially in immunocompromised patients, and the limited therapeutic options require new approaches to replenish the drug discovery pipeline with novel potential drug candidates that might respond to these unmet clinical needs (Roemer and Krysan, 2014). More than 42% of Chemical Diversity in Fungal Co-culture known bioactive compounds have been described as produced by filamentous fungi and many of these molecules with pharmacological applications were developed to the clinic and have been broadly used as antibiotics and antifungals among other applications (Demain, 2014; Schueffler and Anke, 2014). Mining of fungal genomes has revealed the high number of gene clusters involved in the biosynthesis of fungal SMs (SMs) that are not detected in strains cultivated in laboratory conditions and many approaches have been proposed in the recent years to (Brakhage et al, 2008; Rank et al, 2010)
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