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Synthetic Peptide May Succeed Where Antibiotics Have Met with Resistance

The disturbing rise of antibiotic resistance illustrates a need for alternative methods to fight bacterial infections. One potential source of recruits is peptides, molecules composed of amino acid chains. Scientists have discovered more than 200 natural antimicrobial peptides in both plants and animals. Now researchers at the Scripps Research Institute in La Jolla, Calif., have synthesized peptides that are successful in clearing up bacterial infections in mice and produce very few toxic side effects. The results appear in today's Nature.

The researchers tweaked the structure of naturally occurring peptides to maximize their lab-made molecule's antimicrobial tendencies. They included more D-amino acids, which are rare in nature compared to mirror-image L-amino acids, and assembled six- or eight-member ring structures. Then they tested different varieties of the peptides by changing three hydrophilic, or water loving, amino acids within the cyclical molecules. The researchers first measured the efficacy of the various peptides against two bacterial strains in vitro.

Next the team tested three potential versions of the cyclic peptide in mice. They injected the animals with a lethal dose of methicillin-resistant Staphylococcus aureus (MRSA), a pathogen implicated in two million infections that require hospitalization annually. They discovered that the mice survived if they received a certain dose of the peptide injection between 45 minutes and one hour after the initial infection.

Previous attempts to manufacture antimicrobial peptides were hampered because the peptides, which are rather large compared with conventional antibiotics, migrated to the site of infection very slowly. The new class of compounds, the researchers say, "may be able to self-assemble in bacterial membranes and exert antibacterial activity by increasing the membrane permeability." In essence, the cyclic peptides stack themselves in tubes and puncture the wall of a bacterial cell, killing it.

The compounds, the authors write, "offer an attractive complement to the current arsenal of naturally derived antibiotics, and hold considerable potential in combating a variety of existing and emerging diseases."

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