Enantiomer-dependent biodistribution and exposure determine the in vivo behavior of a pleurocidin-derived antimicrobial peptide.

Enantiomer stereochemistry influences systemic distribution and exposure of antimicrobial peptides, with D-enantiomers showing reduced clearance and increased in vivo exposure.

• Why it matters: Understanding how pharmacokinetics and host context affect antimicrobial peptide efficacy is crucial because rapid in vitro bactericidal activity does not necessarily predict in vivo success, hindering clinical translation.
• What they did: The study used fluorescently labeled enantiomers and mouse pneumonia models to examine how stereochemistry impacts biodistribution, systemic exposure, and early bacterial clearance, focusing on pleurocidin-derived peptides.
• The result: Despite improved systemic exposure with D-enantiomers, early bacterial burden reduction was not observed, but exposure-dependent modulation of host immune response occurred, emphasizing the importance of pharmacokinetics and infection context in antimicrobial peptide efficacy.