Roundworm Bacteria Research Shows Promise for Development of New Antibiotics

In a finding that bodes well for the development of new human antibiotics, Harvard researchers have determined the identity of the trigger that causes roundworm bacteria to excrete virulent substances.

Harvard Medical School Professor Jon Clardy teamed with researchers in the department of biological chemistry and molecular pharmacology to pinpoint the amino acid proline—a component of hemolymph, or insect blood—as the trigger for the transformation of roundworm bacteria from dormant to virulent, eliciting comparisons of the bacteria to Dr. Jekyll and Mr. Hyde.

The two groups of bacteria, called Photorhabdus and Xenorhabdus, reside dormant in the gut of roundworms—also called nematodes—until they are “switched on” to excrete antibiotics, digestive enzymes, and insecticidal toxins.

The mixture allows roundworms to launch “a pathogenic attack” against the insect larvae and to subsequently consume it as food, according to the study’s co-author Renee Kontnik, a BCMP research assistant.

“Proline charges the bacteria’s proton motive force, and that’s what gives the microbe the energy to be virulent and produce the toxins,” said co-author Jason M. Crawford, a BCMP research fellow.

Researchers said that the ability to manipulate the trigger causing the bacteria to release virulent factors suggests the possibility of discovering a method to “switch off” the release of harmful substances in the human body.

In addition, the discovery may provide leads in the search for other antibiotic compounds produced by bacteria, according to Kontnik.

“Since the discovery of penicillin, scientists have been looking at the same types of bugs and finding the same compounds, which is problematic because the rediscovery rate is so high,” Crawford said.

“We were looking for methods to turn on the production of new encoded molecules as a drug discovery platform, which would eventually allow science to find new small molecules that lead to the new big antibiotic,” Crawford added.

HMS Professor Raghu Kalluri, who is associated with the BCMP department, said that the discovery of the proline trigger will serve as a useful example for scientists seeking to understand how cancer cells evolve and also how normal cells are co-opted by cancer cells in a given organ.

When normal cells are hijacked by cancer cells, the natural substances are similarly triggered to aid the proliferation of the cancer. Just as the Harvard scientists were searching for the transforming factor in the case of the roundworm, the trigger of how normal cells aid cancer cells in becoming lethal tumors is “the unknown everybody is going after right now in cancer research,” Kalluri said.

“Nature’s role is absolutely relevant,” he added. “Understanding how our body protects against disease and harnessing that protection to shore up the body’s natural defense mechanisms is the best way to protect against disease.”