Targeting Intracellular Pathogenic Bacteria with Unnatural Proline‐Rich Peptides: Coupling Antibacterial Activity with Macrophage Penetration

Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide

“…The antibacterial activity of P14LRR has previously been shown to occur in a non-membrane lytic fashion. 15 We also investigated if the P14KanS and P14KanC conjugates disrupted bacteria membranes by monitoring β-galactosidase release from E. coli upon addition of the conjugates. At five times their MIC values, no significant release of β-galactosidase was observed (Figure S9), whereas melittin at 5 times its MIC displayed a substantial level of release as has previously been shown.…”

“…12–13 Recently a non-cleavable conjugate of methotrexate and a short cell penetrating peptide was demonstrated to target intracellular Listeria , 14 whereas a cell penetrating peptide with intrinsic antimicrobial activity, Fl-P R P R P L -4 (or P14LRR ), was shown to target intracellular Salmonella and Brucella . 15 This latter peptide forms a cationic amphiphilic polyproline helix and is a non-membrane lytic, broad spectrum antibiotic. While both of these peptide-based agents display a good reduction in intracellular bacteria, much more potent agents are needed to effectively eradicate pathogenic bacteria from mammalian cells.…”

Designed supramolecular filamentous peptides: balance of nanostructure, cytotoxicity and antimicrobial activity

“…1 A large number of AMPs consisting of both natural and non-natural amino acids have been de novo designed. 2 In the past, the majority of work has focused on sequence variation and structural optimization of single peptide chains to achieve a balance between antimicrobial efficiency and selectivity. Successful design has and will continue to advance topical application of AMPs in clinically relevant settings.…”

“…Peptides consisting of non-natural amino acids, such as D-amino acids, 12 β-amino acids, 2i, 2l α/γ-AA amino acids, 2f, 13 and peptoids 14 have been successfully designed and synthesized to solve the issue of protease stability, although the cost of their production may be prohibitive for general widespread use. More recently, peptide nanofilaments and nanobeacons were shown to have different enzymatic degradation rates.…”

Dimeric unnatural polyproline-rich peptides with enhanced antibacterial activity

“…19,28 Inspired by these motifs, we recently reported the design of an unnatural polyproline-rich peptide ( FL-P L P R P R -4 ), with broad-spectrum activity against Gram-positive and Gram–negative bacteria. 29 FL-P L P R P R -4 is composed of repeating units of modified proline residues containing either hydrophobic isobutyl groups (P L ) or positively charged guanidinium groups (P R ). The peptide forms a cationic amphiphilic PPII helix (CAPH) with a hydrophobic face composed of 5 isobutyl groups, and a hydrophilic face, composed of 8 guanidinium groups (Fig.…”