Antimicrobial peptides

Abstract

The rapid increase in drug-resistant infections has presented a serious challenge to antimicrobial therapies. The failure of the most potent antibiotics to kill "superbugs" emphasizes the urgent need to develop other control agents. Here we review the history and new development of antimicrobial peptides (AMPs), a growing class of natural and synthetic peptides with a wide spectrum of targets including viruses, bacteria, fungi, and parasites. We summarize the major types of AMPs, their modes of action, and the common mechanisms of AMP resistance. In addition, we discuss the principles for designing effective AMPs and the potential of using AMPs to control biofilms (multicellular structures of bacteria embedded in extracellular matrixes) and persister cells (dormant phenotypic variants of bacterial cells that are highly tolerant to antibiotics).

Figure 1

Schematic representation of an α-helical AMP. This figure assumes the same α-helix propensity for all amino acids in the peptide structure. (A) Helical wheel projection of the AMP (top view). The angle between two consecutive amino acids in the sequence is 100 degree. Dotted lines show two adjacent amino acids in the primary structure. (B) Side view of the peptide. The distance between two adjacent amino acids, “n”, is 0.15 nm.

Figure 2

Schematic representation of some action mechanisms of membrane-active AMPs.(A) Barrel-Stave model. AMP molecules insert themselves into the membrane perpendicularly. (B) Carpet model. Small areas of the membrane are coated with AMP molecules with hydrophobic sides facing inward leaving pores behind in the membrane. (C) Toroidal pore model. This model resembles the Barrel-stave model, but AMPs are always in contact with phospholipid head groups of the membrane. The blue color represents the hydrophobic portions of AMPs, while the red color represents the hydrophilic parts of the AMPs.

Figure 3

Schematic representation of AMP resistance mechanisms. (A) Gram-positive bacteria resist AMPs via teichoic acid modification of LPS molecules and l-lysine modification of phospholipids. (B) Gram-negative bacteria resist AMPs by modifying LPS molecules with aminoarabinose or acylation of Lipid A unit of LPS molecules. (C) Bacteria express some positively charged proteins and integrate them in the membrane so positive charges repulse each other and bacteria can resist such AMPs. (D) Bacteria produce negatively charged proteins and secrete them into extracellular environment to bind and block AMPs. (E) The intracellular AMPs are extruded by efflux pumps. (F) The AMPs inside the cell are degraded by proteases.