The Biological Activities of Polyether Ionophore Antibiotic Routiennocin is Independent of Absolute Stereochemistry

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Abstract

Carboxylic polyether ionophores (CPIs) are among the most prevalent agricultural antibiotics (notably in the US) and these compounds have been in use for decades. The potential to reposition CPIs beyond veterinary use, e. g. through chemical modifications to enhance their selectivity window, is an exciting challenge and opportunity, considering their general resilience towards resistance development. Given the very large societal impact of these somewhat controversial compounds, it is surprising that many aspects of their mechanisms and activities in cells remain unclear. Here, we report comparative biological activities of the CPI routiennocin and two stereoisomers, including its enantiomer. We used an efficient convergent synthesis strategy to access the compounds and conducted a broad survey of antibacterial activities against planktonic cells and biofilms as well as the compounds’ effects on mammalian cells, the latter assessed both via standard cell viability assays and broad morphological profiling. Interestingly, similar bioactivity of the enantiomeric pair was observed across all assays, strongly suggesting that chiral interactions do not play a decisive role in the mode of action. Overall, our findings are consistent with a mechanistic model involving highly dynamic behaviour of CPIs in biological membranes.

Original languageEnglish
Article numbere202400013
JournalChemBioChem
Volume25
Issue7
Number of pages6
ISSN1439-4227
DOIs
Publication statusPublished - Apr 2024

Keywords

  • Antibiotics
  • Antimicrobial Resistance
  • Ionophore
  • Stereochemistry
  • Total synthesis
  • Polyether Polyketides
  • Ionophores/chemistry
  • Animals
  • Mammals/metabolism
  • Anti-Bacterial Agents/pharmacology

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