Traditional antibiotics can work against microbes via different mechanisms. Examples include interference with nucleic acid synthesis, the folate metabolism, inhibition of cell-wall synthesis, and ribosomal binding [1]. However, one problem with this strategy is that the bacteria can readily develop resistance to these conventional antibiotics and the need for new antibiotics becomes more pressing [2, 3].
To solve this problem, people turned their eyes into the natural world and try to find the answer there. As every body knows, the animals and plants live harmoniously with microbes. And it was found that they achieved that due to the help of natural antimicrobial peptides (AMP) which target the cell membrane and can act selectively against bacterial cells and host cells [3]. These natural antimicrobial peptides (AMP) are found to be an effective evolutionary weapon of ancient origin and widely distributed among the multicellular organisms [3] and may be promising pharmaceuticals for treating antibiotic-resistant infections.
Generally, these natural AMPs can be classified into three groups [3, 4]: The linear peptides with α-helical conformation like cecropin found in silk moth and magainin found in frog; peptides containing β-sheet stabilized by disulfied bonds, like defensins found in animals and human, and bactenecin 1 found in cow; and peptides enriched with certain amino acids (for example, indolicidin shown here is predominated by tryptophan, PR-39 is rich in proline and arginine). Further study on their working mechanism and structures revealed that, though these AMPs diverse so great on their sources, sequences, lengths, charges, etc, most of them share two common fundamental structural motifs – amphipathic and cationic [3, 4].
Starting from this point, people developed many synthetic antimicrobial trying to mimic the overall structure of their natural analogs and aim to achieve similar physiological activity. Typically, these synthetic antimicrobial molecules are amphipathic and cationic and exhibit varying degrees of antimicrobial activities. These synthetic antimicrobial molecules can be classified into two main categories. Belonging to the first type are the synthetic peptides mimicking the overall structure and activity of natural AMPs [5-10]. And the second type is synthetic non-peptide molecules which represent polymeric system based on amide bonds, polyphenylene ethylene, pyridinium polymers, polystyrene derivatives, etc. [11-19].
Though many accomplishments have already been achieved, the detailed mechanism of these natural AMPs and their synthetic derivatives remains unknown. The present understanding based on the information people have up to now is that the antimicrobial attack the difference between bacterial cell membranes and host cell membranes [3, 20]. And it is the peptide-lipid interaction that mediates most bacterial-killing process [3, 20]. In a prototypic animal cell membrane, the lipids are distributed asymmetrically between its outer leaflet and inner leaflet. The outer leaflet is dominated by PC and cholesterol, while acidic phosphatidylserine (PS) and most PE sit in the inner leaflet [21]. Such a structure makes it only have weak hydrophobic interactions with cationic antimicrobial peptide. On the other hand, a prototypic membrane of bacterial cells is enriched with neutral PE and acidic PG and cardiolipin. And these lipids are distributed almost randomly on both of its leaflets. Such a structure enables the bacterial cell membrane have strong electrostatic and hydrophobic interactions with cationic antimicrobial peptide. To further our understanding of the peptide-lipid interaction, three models were proposed.
Two of them are similar and based on the foremation of aqueous pores. One is the barrel-stave model [22]. According to this model, the peptides attach to the membrane via electrostatic interactions. On the membrane surface, the peptides adopt α-helical conformation and self-assemble into bundles. Then the bundles insert into the membrane and form the pores by placing their hydrophobic part in contact with the hydrophobic core of membrane. The second one is the toroidal-pore model [4, 23]. Similar to the barrel-stave model, the peptides attach to the membrane via electrostatic interactions. On the membrane surface, the peptides adopt α-helical conformation. But there is no bundle formation. Instead, α-helical peptides keep their hydrophilic part contacting with the hydrophilic head groups of lipid membrane and bend the membrane to form pores. In toroidal-pore model, peptides are associated with lipid head groups during the whole process.
Another important current model is the carpet model [4, 22, 24]. According to this model, the membrane has a curvature of zero at first and the peptides bind preferentially to the lipid head groups. On the membrane surface, the peptides do reorientation and realignment and let their hydrophilic surface facing lipid head groups while hydrophobic facing the hydrophobic core of membrane. Once a critical local concentration is reached, transient holes formed in the membrane and a positive curvature is generated. This step leads to the collapse of the membrane. In this model, α-helical conformation is not a preliminary requirement.