Insect Antibiotics -- Resistance Is Futile! Cecropin A Bypasses Outer Defenses To Kill Bacteria From The Inside

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.