Polyether Ionophore Antibiotics Target Drug-Resistant Clinical Isolates, Persister Cells, and Biofilms

Malene Wollesen, Kasper Mikkelsen, Marie Selch Tvilum, Martin Vestergaard, Mikala Wang, Rikke L Meyer, Hanne Ingmer, Thomas Poulsen, Thomas Tørring

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

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 being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight 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. IMPORTANCE Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.

Original languageEnglish
Article numbere0062523
JournalMicrobiology spectrum
Volume11
Issue4
Number of pages14
ISSN2165-0497
DOIs
Publication statusPublished - Aug 2023

Keywords

  • Animals
  • Anti-Bacterial Agents/therapeutic use
  • Anti-Infective Agents/pharmacology
  • Biofilms
  • Cattle
  • Gram-Positive Bacteria
  • Humans
  • Ionophores/pharmacology
  • Microbial Sensitivity Tests
  • ionophore
  • antimicrobial resistance
  • biofilm
  • natural antimicrobial products
  • antibiotics
  • Staphylococcus aureus
  • persister cells

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