Antimicrobial Peptides

With bacterial resistance and emerging infectious diseases becoming potential threats to humans, ribosomally synthesized antimicrobial peptides have become a promising focus area in antibiotic research. Antimicrobial peptides are classified as either non-ribosomally synthesized peptides or ribosomally synthesized peptides (RAMPs). Non-ribosomally synthesized peptides are found in bacteria and fungi. These antimicrobial peptides are assembled by peptide synthetases as opposed to ribosomal-supported synthesis. Gramicidin, bacitracin, polymyxin B, and vancomycin are examples of non-ribosomally synthesized antimicrobial peptides. These antibiotics are proven to be effective research tools, but compared to RAMPs they are disadvantageous for novel applications due to emerging bacterial resistance, for example vancomycin-resistant Staphylococcus aureus and enterococci. RAMPs are derived from a diverse range of species, from prokaryotes to humans. Antimicrobial peptides comprise a host's natural defense against the daily exposure to millions of potential pathogens. These peptides may also possess antiviral, antiparasitic, and antineoplastic activities. Over 500 RAMPs have been described in the literature. Their unique antibiotic spectrum is determined by amino acid sequence and structural conformation. RAMPs are gene-encoded peptides consisting of 12-50 amino acids with very little genetic overlap. A lack of sequence homology between RAMPs is indicative of evolutionary optimization of form and function in the species environment. RAMPs are typically cationic peptides with at least half of the amino acid residues being hydrophobic and a smaller number of neutral or negatively charged residues. Their amphipathic structure with opposing hydrophobic and lipohphilic faces aids in the perturbation of the bacterial cell wall. The mechanism of action of a RAMP involves peptide binding to the bacterial cell surface, conformational change to the peptide, aggregation of multiple peptide monomers, and pore formation through the bacterial cell wall. RAMPs bind to lipopolysaccharides in the negatively-charged, Gram-negative bacterial outer cell wall or to the acidic polysaccharides of the Gram-positive bacterial outer cell wall. After binding, permeabilization of the bilayer membrane occurs by transient pore creation. Permeabilization leads to a leakage of cell components and cell death. There are several models of permeabilization although the precise mechanism is unknown. Three permeabilization models are termed barrel-stave, thoroidal, and carpet. Figure 1. depicts bacterial cell wall perturbation by a RAMP.