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

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

doi:10.3390/molecules24061121

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

^1,†

¹,

²,

^1,‡

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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Denmark

Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark

⁴

Department of Pathobiology and Population Sciences, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK

Author to whom correspondence should be addressed.

^†

Present address: Department of Food Science, Faculty of Science, University of Copenhagen, Rolighedsvej 30, 1958 Frederiksberg, Denmark.

^‡

Present address: Department of Science and Environment, Roskilde University, Universitetsvej 1, 4000 Roskilde, Denmark.

^§

Present address: Novo Nordisk A/S, Krogshøjvej 44, 2820 Bagsværd, Denmark.

Molecules 2019, 24(6), 1121; https://doi.org/10.3390/molecules24061121

Received: 18 February 2019 / Revised: 12 March 2019 / Accepted: 12 March 2019 / Published: 21 March 2019

(This article belongs to the Section Bioorganic Chemistry)

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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

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MDPI and ACS Style

Greco, I.; Hansen, J.E.; Jana, B.; Molchanova, N.; Oddo, A.; Thulstrup, P.W.; Damborg, P.; Guardabassi, L.; Hansen, P.R. Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues. Molecules 2019, 24, 1121. https://doi.org/10.3390/molecules24061121

AMA Style

Greco I, Hansen JE, Jana B, Molchanova N, Oddo A, Thulstrup PW, Damborg P, Guardabassi L, Hansen PR. Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues. Molecules. 2019; 24(6):1121. https://doi.org/10.3390/molecules24061121

Chicago/Turabian Style

Greco, Ines, Johannes E. Hansen, Bimal Jana, Natalia Molchanova, Alberto Oddo, Peter W. Thulstrup, Peter Damborg, Luca Guardabassi, and Paul R. Hansen. 2019. "Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues" Molecules 24, no. 6: 1121. https://doi.org/10.3390/molecules24061121

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

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