Proline-rich antimicrobial peptides: converging to a non-lytic mechanism of action

Abstract

Proline-rich antimicrobial peptides are a group of cationic host defense peptides of vertebrates and invertebrates characterized by a high content of proline residues, often associated with arginine residues in repeated motifs. Those isolated from some mammalian and insect species, although not evolutionarily related, use a similar mechanism to selectively kill Gram-negative bacteria, with a low toxicity to animals. Unlike other types of antimicrobial peptides, their mode of action does not involve the lysis of bacterial membranes but entails penetration into susceptible cells, where they then act intracellularly. Some aspects of the transport system and cytoplasmic targets have been elucidated. These features make them attractive both as anti-infective lead compounds and as a new class of potential cell-penetrating peptides capable of internalising membrane-impermeant drugs into both bacterial and eukaryotic cells.

Fig. 1

Model for the mode-of-action of mammalian and insect PR-AMPs. PR-AMPs like Bac7 and apidaecin can penetrate into susceptible bacterial cells in a stereoselective manner using a transport system involving the membrane protein Sbma/BacA, likely part of an ABC transport system for which the oligomerization state and other interactors are as yet unknown. The natural all-L PR-AMPs are internalized by this system at sub- to low micromolar concentration, while the all-D enantiomers are not. At considerably higher concentrations, both L- and D-isomers of PR-AMPs like Bac7 are capable of killing bacteria via a membranolytic mechanism. Other, as yet unknown, transporters may internalize these peptides at intermediate concentrations. Once internalized, PR-AMPs such as pyrrhocoricin and Bac7 can interact with the bacterial chaperone DnaK, affecting the ATPase activity or its peptide binding domain (PBD) or both. There are likely also other intracellular interactors, alongside the chaperone, or downstream from it