Abstract
Proline‐rich antimicrobial peptides (PrAMPs) are promising agents to combat multi‐drug resistant pathogens due to a high antimicrobial activity, yet low cytotoxicity. A library of derivatives of the PrAMP Bac5(1–17) was synthesized and screened to identify which residues are relevant for its activity. In this way, we discovered that two central motifs ‐PIRXP‐ cannot be modified, while residues at N‐ and C‐ termini tolerated some variations. We found five Bac5(1–17) derivatives bearing 1–5 substitutions, with an increased number of arginine and/or tryptophan residues, exhibiting improved antimicrobial activity and broader spectrum of activity while retaining low cytotoxicity toward eukaryotic cells. Transcription/translation and bacterial membrane permeabilization assays showed that these new derivatives still retained the ability to strongly inhibit bacterial protein synthesis, but also acquired permeabilizing activity to different degrees. These new Bac5(1–17) derivatives therefore show a dual mode of action which could hinder the selection of bacterial resistance against these molecules.
Highlights
Multi-drug resistant (MDR) pathogens are a concerning health problem worldwide that will seriously compromise many medical procedures, from routine to life-saving treatments [1]
The seventeen Bac5(1-17) derivatives were tested for their capability to inhibit protein synthesis in vitro using coupled transcription/translation assays [6a, 6f, 7c, 8a, 8b, 11b] as well as to inhibit the growth of E. coli cells using minimal inhibitory concentration (MIC) assays in Müller-Hinton broth (MH) (Fig. 1)
This is emphasized by the 281 and 291 peptides which had superior MIC values (4 μM) and yet were respectively significantly worse and slightly worse inhibitors than wild type Bac5(1-17) in the transcription/translation assay (Fig. 2). These findings suggest that the improved antimicrobial activity of the substituted Bac5(1-17) derivatives compared to the wild type Bac5(1-17) peptide is not due to an improved ability to bind to ribosomes and inhibit the translation (Figure 2)
Summary
FULL PAPER Proline-rich peptides with improved antimicrobial activity against E. coli, K. pneumoniae and A. baumannii. Dr Mario Mardirossiana, Riccardo Solaa, Dr Bertrand Beckertb, Dr Dominic W.
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