Structure-Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues

Ines Greco, Johannes E. Hansen, Bimal Jana, Natalia Molchanova, Alberto Oddo, Peter Waaben Thulstrup, Peter Damborg, Luca Guardabassi, Paul R. Hansen*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) constitutes an emerging health problem for companion animals in veterinary medicine. Therefore, discovery of novel antimicrobial agents for treatment of Staphylococcus-associated canine infections is urgently needed to reduce use of human antibiotics in veterinary medicine. In the present work, we characterized the antimicrobial activity of the peptoid D2 against S. pseudintermedius and Pseudomonas aeruginosa, which is another common integumentary pathogen in dogs. Furthermore, we performed a structure–activity relationship study of D2, which included 19 peptide/peptoid analogs. Our best compound D2D, an all d-peptide analogue, showed potent minimum inhibitory concentrations (MICs) against canine S. pseudintermedius (2–4 µg/mL) and P. aeruginosa (4 µg/mL) isolates as well as other selected dog pathogens (2–16 µg/mL). Time–kill assays demonstrated that D2D was able to inhibit MRSP in 30 min at 1× MIC, significantly faster than D2. Our results suggest that at high concentrations D2D is rapidly lysing the bacterial membrane while D2 is inhibiting macromolecular synthesis. We probed the mechanism of action at sub-MIC concentrations of D2, D2D, the l-peptide analog and its retro analog by a macromolecular biosynthesis assay and fluorescence spectroscopy. Our data suggest that at sub-MIC concentrations D2D is membrane inactive and primarily works by cell wall inhibition, while the other compounds mainly act on the bacterial membrane. View Full-Text
Keywords: antimicrobial; peptide; peptoid; mode of action; canine infections; methicillin-resistant Staphylococcus pseudintermedius; Pseudomonas aeruginosa
OriginalsprogEngelsk
TidsskriftMolecules
Vol/bind24
Udgave nummer6
ISSN1420-3049
DOI
StatusUdgivet - 2019

Emneord

  • Antimicrobial
  • Peptide
  • Peptoid
  • Mode of action
  • Canine infections
  • Methicillin-resistant Staphylococcus pseudintermedius
  • Pseudomonas aeruginosa

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