Cyclic peptide antibiotics; self-assembly required

Abstract

Bacterial resistance to conventional antibiotics has become a serious problem in infection control. Now, Fernandez-Lopez and colleagues 1 Fernandez-Lopez S. et al. Antibacterial agents based on the cyclic d,l-α-peptide architecture. Nature. 2001; 412: 452-455 Crossref PubMed Scopus (834) Google Scholar have shown that certain types of peptides, those with a particular sequence and a cyclic d,l-α-peptide structure, can actually kill Gram-positive and Gram-negative bacteria. These cyclic peptides, with an even number of d- and l-α amino acids, form flat ring-like structures that can stack into hollow tubes in the membrane of bacteria. A panel of peptides designed for the formation of these structures and with specificity for negatively charged bacterial membranes was tested for in vitro inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, as well as the undesirable propensity to lyse blood cells. The activity of a few of the most promising peptides was investigated in greater detail. By attenuated total reflectance Fourier transform-infrared spectroscopy (ATR/FT-IR) analysis, it was shown that each of these peptides was able to self-assemble forming tubes in synthetic lipid membranes. These peptides caused depolarization of intact bacteria as measured by monitoring release of a dye incorporated into SA membranes. Pore formation leading to membrane leakage is probably the mode of action of these peptides. Most importantly, the peptides were able to protect mice from lethal infections with MRSA. This was determined by infecting mice and, after 45–60 minutes, treating them with various doses of peptides. The 50%-protective dose ranged from about 5–10 mg kg−1; this efficacy paralleled the in vitro bactericidal activities of each peptide tested. These peptides were well tolerated and appeared to have no deleterious effects. The rapid action of these peptides, coupled with the fact that they act on membrane integrity rather than on vital biosynthetic processes, suggests that resistance to this type of agent could be slower to develop. Thus, these novel peptides with their unusual structures might represent our next generation of antibiotics.