D-Enantiomeric Peptides that Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect against Lethal Pseudomonas aeruginosa Infections

César De La Fuente-Núñez, Fany Reffuveille, Sarah C. Mansour, Shauna L. Reckseidler-Zenteno, Diego Hernández, Gilles Brackman, Tom Coenye, Robert E.W. Hancock

    Research output: Contribution to journalJournal Articlepeer-review

    241 Citations (Scopus)

    Abstract

    In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo.

    Original languageEnglish
    Pages (from-to)196-205
    Number of pages10
    JournalChemistry and Biology
    Volume22
    Issue number2
    DOIs
    Publication statusPublished - 19 Feb. 2015

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