Polyether ionophore antibiotics target drug-resistant clinical isolates, persister cells, and biofilms

Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture, e.g. as anti-coccidiostats, and have potent antibacterial activity, they are not currently pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they differ significantly in structure, and for this reason, it remains unclear how structure and activity are related. To triage whether certain members of the family constitute particularly interesting springboards for in-depth investigations, and future synthetic optimization, we here conduct a systematic comparative study of nine different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development.