Abstract
The synthetic cyclic hexapeptide cWFW (cyclo(RRRWFW)) has a rapid bactericidal activity against both Gram-positive and Gram-negative bacteria. Its detailed mode of action has, however, remained elusive. In contrast to most antimicrobial peptides, cWFW neither permeabilizes the membrane nor translocates to the cytoplasm. Using a combination of proteome analysis, fluorescence microscopy, and membrane analysis we show that cWFW instead triggers a rapid reduction of membrane fluidity both in live Bacillus subtilis cells and in model membranes. This immediate activity is accompanied by formation of distinct membrane domains which differ in local membrane fluidity, and which severely disrupts membrane protein organisation by segregating peripheral and integral proteins into domains of different rigidity. These major membrane disturbances cause specific inhibition of cell wall synthesis, and trigger autolysis. This novel antibacterial mode of action holds a low risk to induce bacterial resistance, and provides valuable information for the design of new synthetic antimicrobial peptides.
Highlights
Antimicrobial peptides (AMPs) have been in the focus of research attention as a promising alternative for conventional antibiotics[1]
In agreement with the cytoplasmic membrane as the likely cellular target[6], cWFW elicited a typical cell envelope stress response characterised by upregulation of proteins controlled by the extracytoplasmic function (ECF) sigma factors SigM, SigW and SigX (Table 1)
We have analysed the mode of action of the small cyclic antimicrobial membrane-targeting peptide cWFW
Summary
Antimicrobial peptides (AMPs) have been in the focus of research attention as a promising alternative for conventional antibiotics[1]. As first postulated by Epand and Epand[7], short cationic AMPs might, as an alternative mechanism, induce clustering of anionic lipids within the bacterial membrane due to electrostatic interactions[8] This effect, which is highly dependent on the phospholipid composition and requires the presence of both negatively charged and zwitterionic lipid species, could later be confirmed for small cyclic hexapeptides including cWFW in vitro[9,10]. Whether this clustering takes place in vivo, and whether it contributes to the antibacterial activity of cWFW has so far remained unanswered. We consider these effects as a novel mechanism of action for antimicrobial peptides, and discuss the implication on antimicrobial resistance
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