February 5, 2003
Insect Antibiotics - Resistance is
Futile!
Insect Antibiotic, Cecropin A, Bypasses Outer Defenses
to Kill Bacteria From The Inside
(Philadelphia,
PA) - For antibiotics, the best way to beat bacterial
defenses may be to avoid them altogether. Researchers
at University of Pennsylvania School of Medicine
have discovered that Cecropin A, a member of a family
of antibiotic proteins produced by insects, may kill
bacteria and avoid resistance by entering bacterial
cells and taking control of their genetic machinery.
While most antibiotics kill bacteria by attacking critical
enzyme systems, Cecropin A somehow slips inside the
bacteria and turns specific genes on and off. The findings
challenge conventional thinking on how these antibiotics
function, and may aid in turning antimicrobial peptides
like Cecropin A into therapeutic agents.
"For decades, researchers have studied Cecropin
A and focused on its obvious effects against bacterial
cell walls and membranes. These antibiotics certainly
do disrupt outer structures of the bacterial cell, but
there's much more to the story," said Paul H.
Axelsen, M.D., an associate professor in the Department
of Pharmacology and Division of Infectious Diseases
at Penn. "Before the bacterial cell dies, Cecropin
A enters the cell and alters the way its genes are regulated.
It's like sneaking over the castle wall and opening
the gates from the inside. We need to understand this
mechanism of action because it may explain why bacteria
are unable to develop resistance to this family of antibiotics."
Axelsen's findings were described in the January issue
of the Antimicrobial Agents and Chemotherapy,
a publication of the American Society for Microbiology.
In their study, Axelsen and his colleagues treated E.
coli with small doses of Cecropin A - not enough
to kill the bacteria, but enough to see what genes are
affected when bacteria are exposed to the antibiotic.
They found that transcript levels for 26 genes are affected,
11 of which code for proteins whose functions are unknown.
Even more surprising for the researchers, the genes
are not the same as the ones affected when bacteria
experience nutritional, thermal, osmotic, or oxidative
stress.
"It is a whole different mechanism by which to
kill bacteria, and one that we still have yet to completely
figure out," said Axelsen. "How Cecropin A
turns these genes on and, indeed, how it gets inside
E. coli in the first place, is still something
of a mystery."
Despite years of research, there remains much to know
about the antibiotics produced by insects. Cecropin
A was discovered in the Cecropia moth, also known as
the silkworm moth, the largest moth in North America.
Since insects do not have an immune system as humans
do, they rely on polypeptide antibiotics like Cecropin
A to fight off infections. These proteins are highly
selective - they readily kill bacteria, but are harmless
to human and other animal cells. Moreover, bacteria
that are susceptible initially stay susceptible - researchers
have not seen bacteria develop resistance to their action.
For this reason, these antibiotics offer a potentially
invaluable model for new therapeutic agents.
"We're engaged in an arms race against infectious
bacteria. With each new antibiotic, bacteria have found
a way to evolve resistance - primarily by slightly altering
cellular enzymes," said Axelsen. "Bacteria
may be unable to alter their genetic machinery, and
this may explain why strains of bacteria resistant to
Cecropin A do not arise."
Funding for this research was supported by grants from
the National Institutes of Health and the American Heart
Association, and from Affymetrix's generous donation
of E. coli GeneChip Microarrays.
# # #
Editor's Note: Dr. Axelsen does not have
any financial stake in Affymetrix.
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