Chemical genomics reveals mechanistic hypotheses for uncharacterized bioactive molecules in bacteria

- Chemical-genomics provides mechanistic hypotheses for bioactive compounds of unknown function.
- Genetic enhancement and suppression profiles can be useful as target lists for downstream chemical screening.
- Deep-sequencing of suppressor mutants can provide strong evidence for cellular target.

In an effort to combat the perpetual emergence of new antibiotic-resistant human pathogens, research in industry and academe aims to find new means of controlling infection. The discovery of new antimicrobial chemicals is not the bottleneck in an era where high-throughput screening rapidly uncovers new bioactive compounds. Rather, the rate-limiting step in antimicrobial discovery pipelines is identifying mechanisms of action (MOA) of bioactive molecules produced by these increasingly large-scale efforts. Chemical genomics has proven to be of high value in providing mechanistic hypotheses for novel bioactive chemical matter. Several techniques fall under this blanket term, including interactions with deletion or transposon libraries, fluorescent or luminescent reporter library profiles, or deep sequencing approaches. Each of these provide unique and complementary outputs, and have high value in generating target lists for chemical screens, or assisting in downstream MOA discovery. We review here the broad usefulness of this technique to aid in MOA determination, to identify targets for new lead molecules, and to expand our mechanistic understanding of existing drugs.