Finding new microbial secondary metabolites

Some bacteria harbor many so-called silent or cryptic gene clusters that aren’t active under typical lab conditions. Secondary metabolites produced by these gene clusters, ones not directly involved in bacterial growth and development, could be a rich source of new medicines, but researchers need to find those metabolites first. To do that, Mohammad R. Seyedsayamdost and coworkers at Princeton University combine a technique called high-throughput elicitors screening with imaging mass spectrometry (Nat. Chem. Biol. 2019, DOI: 10.1038/s41589-018-0193-2). In this method, the researchers use small molecules to turn on silent gene clusters and identify the resulting metabolites with imaging mass spectrometry. The advantage of the new method is that the metabolites themselves rather than genetic assays are the readout. It works with sequenced and unsequenced bacteria. Using this approach, the Princeton team identified one of the smallest lasso peptides ever reported and two new families of glycopeptides, keratinimicins and keratinicyclins. The latter combines features of glycopeptide antibiotics such as vancomycin with features of oxazolidinone antibiotics such as linezolid, the first time such a combination has been reported. They exhibit potent and specific antiviral activity. In contrast, the keratinimicins exhibit antibacterial activity against multiple Gram-positive bacteria but not against vancomycin-resistant enterococci, which suggests that they may have a similar mode of action as vancomycin.