Proline‐Rich Peptides with Improved Antimicrobial Activity against E. coli, K. pneumoniae, and A. baumannii

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.

Caprine Bactenecins as Promising Tools for Developing New Antimicrobial and Antitumor Drugs

“…These data underline the importance of a comprehensive study of PR-AMPs of higher vertebrates for developing novel immunomodulatory and antimicrobial drugs. To date, the most well studied mammalian PR-AMPs are bovine bactenecins or their fragments, which exert a powerful action against a variety of multidrug-resistant Gram-negative pathogens (Mardirossian et al, 2019a;Price et al, 2019).…”

Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields

“…For instance, Tur1A, which is an orthologous AMP of bovine PrAMP Bac7 discovered from Tursiops truncatus , interferes with the transition from the initial phase to the extension phase of protein synthesis by binding to ribosomes. In addition, different PrAMPs lack a high sequence similarity but have short motifs containing repeating proline and arginine (Arg) residues (e.g., -PPXR- in Bac5 and -PRPX- in Bac7) ( Mardirossian et al, 2018 , 2019 ). Although PrAMPs mainly kill Gram-positive bacteria, p PR-AMP1, a proline-rich AMP identified from crab ( Scylla paramamosain ), exhibits antimicrobial activity against Gram-positive and Gram-negative bacteria ( Imjongjirak et al, 2017 ).…”

(Re)Defining the Proline-Rich Antimicrobial Peptide Family and the Identification of Putative New Members

“…Since their discovery, a number of strategies have been adopted to develop improved PrAMP analogs including the use of consensus sequence analysis, resulting in a de novo A3-APO (All Peptide Optimized) peptide (Otvos et al, 2005 ), and of brute force large library analogs leading to bactenecin 5 derivatives with improved spectrum of activity being developed some 30 years after the discovery of the original bactenecin 5 (Mardirossian et al, 2019 ). Additionally, PrAMPs are of great interest as potential vectors for drug delivery, with pyrrhocoricin, bactenecin 7, and PR-39 each being reported to be cell penetrating peptides and oncocin, apidaecin and drosocin also able to cross the blood-brain barrier (Li et al, 2014 ).…”