TY - JOUR
T1 - The Biological Activities of Polyether Ionophore Antibiotic Routiennocin is Independent of Absolute Stereochemistry
AU - Borcher Møller, Søren Lau
AU - Rasmussen, Michelle H.
AU - Li, Jun
AU - Svenningsen, Esben B.
AU - Wørmer, Gustav J.
AU - Tørring, Thomas
AU - Poulsen, Thomas B.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Antimicrobial Resistance
KW - Ionophore
KW - Stereochemistry
KW - Total synthesis
KW - Polyether Polyketides
KW - Ionophores/chemistry
KW - Animals
KW - Mammals/metabolism
KW - Anti-Bacterial Agents/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85186258684&partnerID=8YFLogxK
U2 - 10.1002/cbic.202400013
DO - 10.1002/cbic.202400013
M3 - Journal article
C2 - 38329925
AN - SCOPUS:85186258684
SN - 1439-4227
VL - 25
JO - ChemBioChem
JF - ChemBioChem
IS - 7
M1 - e202400013
ER -