Abstract
The microbial secondary metabolome encompasses great synthetic diversity, empowering microbes to tune their chemical responses to changing microenvironments. Traditional metabolomics methods are ill-equipped to probe a wide variety of environments or environmental dynamics. Here we introduce a class of microscale culture platforms to analyse chemical diversity of fungal and bacterial secondary metabolomes. By leveraging stable biphasic interfaces to integrate microculture with small molecule isolation via liquid–liquid extraction, we enable metabolomics-scale analysis using mass spectrometry. This platform facilitates exploration of culture microenvironments (including rare media typically inaccessible using established methods), unusual organic solvents for metabolite isolation and microbial mutants. Utilizing Aspergillus, a fungal genus known for its rich secondary metabolism, we characterize the effects of culture geometry and growth matrix on secondary metabolism, highlighting the potential use of microscale systems to unlock unknown or cryptic secondary metabolites for natural products discovery. Finally, we demonstrate the potential for this class of microfluidic systems to study interkingdom communication between fungi and bacteria.
Highlights
The microbial secondary metabolome encompasses great synthetic diversity, empowering microbes to tune their chemical responses to changing microenvironments
We address these obstacles by presenting a microscale platform that simplifies and accelerates the workflow of secondary metabolism studies, allows the exploration of a larger spectrum of microenvironmental cues, and brings salient features of microscale platforms to bear on microbial metabolomics research
Using fungi well known for their rich secondary metabolism, Aspergillus nidulans (A. nidulans) and Aspergillus fumigatus (A. fumigatus), as model systems, we demonstrate the potential of a combinatorial approach to metabolite extraction and microbial culture for microbial metabolomics
Summary
The microbial secondary metabolome encompasses great synthetic diversity, empowering microbes to tune their chemical responses to changing microenvironments. By leveraging stable biphasic interfaces to integrate microculture with small molecule isolation via liquid–liquid extraction, we enable metabolomics-scale analysis using mass spectrometry This platform facilitates exploration of culture microenvironments (including rare media typically inaccessible using established methods), unusual organic solvents for metabolite isolation and microbial mutants. There is a need for a culture method that has a small physical footprint, is efficient to use and is compatible with a passive, reproducible small molecule extraction process We address these obstacles by presenting a microscale platform that simplifies and accelerates the workflow of secondary metabolism studies, allows the exploration of a larger spectrum of microenvironmental cues, and brings salient features of microscale platforms (surface/volume ratios, segregated culture chambers, matrix design) to bear on microbial metabolomics research. We designed an integrated coculture and extraction platform that is capable of performing cultures of fungi and bacteria and further enables studies of chemical interactions between kingdoms
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