Drug discovery: Diversifying complexity.

and position of cyclization was then confirmed through peracylation and NMR spectroscopic analysis of peracylatedjagaricin. Knockout mutants were constructed to provide further confirmation that the jag genes were responsible for jagaricin production, and no jagaricin could be detected when the knockout mutant was grown on mushroom tissue and examined with IMS. Jagaricin’s native biological role was examined by applying the pure compound to mushroom tissue. These tests showed it creates lesions similar to those seen in mushrooms infected with a disease called soft rot. Further antimicrobial screening showed that jagaricin possesses potent antifungal effects against the common human fungal pathogens Candida albicans, Aspergillus fumigatus and A. terreus. Connecting structure to function is notoriously difficult for microbially derived specialized metabolites, but Hertweck and co-workers have successfully demonstrated how IMS can be used to make this connection. Imaging mass spectrometry is a powerful tool that gives researchers rare glimpses of specialized metabolites in their native environments, especially when used in conjunction with efficient identification and characterization strategies such as genome mining. The sensitivity of mass spectrometry enables the detection of specialized metabolites that might not be discovered using standard laboratory culturing methods or by activity-guided isolations. Obtaining enough pure compound to determine the full structure can be a barrier when using IMS to guide discovery of new molecules; however, in this case, the liquid fermentation conditions were amenable to optimization. Ecological therapeutic lead discovery, as exemplified by jagaricin, will be imperative in uncovering novel anti-infectives in the future. However, finding systems that can be adapted to the laboratory setting is crucial. Access to the host was critical in uncovering jagaricin; however ecological discovery becomes increasingly difficult if the biological organism is too large or cannot be cultured in a laboratory setting. Along these same lines, access to genomic data greatly increases the odds of success using ecological discovery — but is not necessarily required. Genome mining can aide in compound identification, but full structure elucidations are still necessary. As tools such as IMS and genome mining become more efficient in providing insights into the ecological roles of specialized metabolites, we may once again, after decades of neglect, gain the upper hand in the battle against human pathogens. ❐