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With minor tinkering, a tiny protein, a peptide from
the skin of a frog could be fashioned into a novel
antibiotic that would lack the toxic byproducts of
some more conventional drugs. More importantly, such
peptides would represent a new class of antibiotics,
at a time when new classes are sorely needed as
resistance rises among existing classes. The
research was published online, 26 January 2015, in
Antimicrobial Agents and Chemotherapy, a journal of
the American Society for Microbiology.
Frog skin is a mucus membrane, the same type of
tissue that lines the oral cavity and the rest of
the gastrointestinal tract. As such, it’s
potentially quite vulnerable to infection; yet frogs
are remarkably resistant, said principal
investigator David Craik, Ph.D., a professor in the
Institute for Molecular Bioscience, the University
of Queensland, Australia. “Their skin is known to
secrete peptides with antimicrobial activity and we
wanted to explore them as potential antibiotics for
human use. However, although those peptides make
great leads for drug discovery, they are often not
stable enough to be used as drugs.”
Craik found that the sequences of peptides from the
frog Rana sevosa (also known as the gopher frog),
closely resemble a cyclic peptide produced in
sunflower seeds that he had studied earlier, which
he said is exceptionally stable. That stability, and
the interest the pharmaceutical industry had already
expressed in peptides’ potential as a new class of
drugs, led him to study the frog peptides.
The research showed that the frog peptides, which
lacked the sunflower peptide’s cyclic structure,
also lacked its stability. The problem is that
non-cyclic peptides are vulnerable to proteases,
digesive enzymes which are designed to cleave the
ends of peptides. “A cyclic peptide has no loose
ends to be clipped by proteases,” said Craik.
So Craik et al. joined the two ends of some frog
peptides and left others linear, and tested both
versions in a mouse model of wound infection. The
linear peptides had powerful activity against
Staphylococcus aureus, a leading cause of skin and
soft tissue infections, which many patients acquire
in hospital. “However, the re-engineered cyclic
molecules lost some of their antibiotic potency,”
said Craik. “We need to do further work to generate
molecules with both potency and stability.”
Even though this is not the first time researchers
have investigated the use of frog skin peptides as
drugs, Craik says this peptide is a relatively small
one and easy to synthesize, the latter having been a
problem in some previous such efforts. Additionally,
the small size means that it is less likely than
larger peptides to generate immune reactions against
itself.
A further, more general advantage of cyclic peptides
as drugs is that unlike many conventional drugs,
their breakdown products, amino acids, the building
blocks from which proteins are made, are harmless.
For more information
American Society For Microbiology
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