Opening up the Single-Cell Toolbox for Microbial Natural Products Research.

The diverse microbes that produce natural products represent an important source of novel therapeutics, drug leads, and scientific tools. However, the vast majority have not been grown in axenic culture and are members of complex communities. While meta-'omic methods such as metagenomics, -transcriptomics, and -proteomics reveal collective molecular features of this "microbial dark matter", the study of individual microbiome members can be challenging. To address these limits, a number of techniques with single-bacterial resolution have been developed in the last decade and a half. While several of these are embraced by microbial ecologists, there has been less use by researchers interested in mining microbes for natural products. In this review, we discuss the available and emerging techniques for targeted single-cell analysis with a particular focus on applications to the discovery and study of natural products.