Antimicrobial Peptides: Mechanisms of Action and Resistance

Abstract

More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide's structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

In Silico Structural Evaluation of Short Cationic Antimicrobial Peptides

“…Interestingly, a clear separation in the disposition of the two sets of residues was noted, with all the positively-charged side chains converging towards one side of the peptide (Figure 9c). This observation complies with the hypothesis that these peptides assume an amphipathic 3D conformation [2], with a charged region responsible for binding to the negatively-charged LPS on the surface of Gram negative bacteria, and a predominantly hydrophobic nature allowing the peptide to then penetrate the membrane. The surface of the centroid VCP-VT1 was also analysed in terms of polarity, and a clear distinction between hydrophilic and hydrophobic areas could be observed (Figure 9d), in accordance with what was discussed for the peptides with experimentally-known conformations.…”

“…To this aim, a library of active peptides with known 3D structures was initially created and clustered and the centroids analyzed. This confirmed the experimental evidence that the majority of these molecules often contain basic amino acid residues in close proximity to aromatic residues and that they assume an amphipathic conformation [2,5]. Furthermore, it was shown that their predicted conformations are in excellent agreement with those experimentally observed in solution.…”

“…Naturally-occurring cationic peptides often possess antimicrobial properties [2] and represent a promising class of lead compounds to be selected for the design of new antibiotics. However, of the nearly 5000 cationic antimicrobial peptides (AMPs) described to date, fewer than 100 are currently undergoing clinical trials [3], possibly due to the challenges related to the development of protein-based drugs.…”

Structure and membrane interactions of the homodimeric antibiotic peptide homotarsinin

“…They have been classified for shared properties that appear to be important for their structure and activity such as their cationic amphipathic character, regions rich in hydrophobic and aromatic residues1314 or intra-chain cystine bonds as described for defensins15 and protegrins16. Whereas a good number of sequences carrying such intra-chain cystine bridges have been described151617, dimeric peptides with inter-chain disulfide bonds are less common with the heterodimeric peptide distinctin being the only example published so far18.…”

Antimicrobial peptide gene expression in periodontitis patients: A pilot study

“…Furthermore, the limitations of conventional antibiotics in the treatment of periodontal disease are well known, especially that of the bacterial resistance induction (Herrera, Alonso, León, Roldán, & Sanz, ). Hence, the development of new therapeutic molecules reproducing AMP functions is particularly appealing considering that it involves low cytotoxicity and no bacterial resistance (Bechinger & Gorr, ; Helmerhorst et al., ; Peters, Shirtliff, & Jabra‐Rizk, ).…”