Health Editor’s Note: Really at this juncture, the issue is not why we have an ever increasing number of drug-resistant germs, but how we can continue to find ways to kill them….Carol
Worm Guts May Hold a New Weapon Against Antibiotic-Resistant Germs
by National Institutes of Health/Allergy and Infectious Diseases
A gruesome fate looms for any caterpillar that gets infected with a certain kind of tiny parasitic roundworm. Commensal Photorhabdus bacteria that live in the worm’s gut release a flood of toxins, enzymes, and antibiotics that blunt the caterpillar’s immune response and turn its tissues into a worm-nourishing soup. What’s bad for a caterpillar, though, may be a boon for people thanks to a recent discovery by NIAID-supported scientist Kim Lewis, Ph.D.
Dr. Lewis and his colleagues at Northeastern University search for new compounds from natural sources to treat antibiotic-resistant bacterial infections. The threat of antibiotic-resistant bacteria, especially those in a category called gram-negative bacteria, is serious and growing. A new report by the Centers for Disease Control and Prevention notes that there are more than 2.8 million antibiotic-resistant infections in the United States each year, and more than 35,000 deaths. Gram-negative bacteria, which include E. coli, Klebsiella pneumoniae, and the bacteria that cause gonorrhea, are especially difficult to treat and the last new class of antibiotics aimed specifically at gram-negative bugs was developed over 50 years ago.
In nature, antibiotics released by Photorhabdus bacteria help to preserve the insect cadaver and fend off competing bacteria from the surroundings, including gram-negative bacteria from the roundworm’s gut. The investigators at Northeastern screened 22 species of Photorhabdus and Xenorhabdus bacteria (commensal gut bacteria found in a different parasitic roundworm) and discovered a compound in one species of Photorhabdus that inhibited the growth of E. coli.
Further characterization of the compound, which they dubbed darobactin, revealed its chemical structure and showed that it has an unusual mode of action that makes it particularly effective against gram-negative bacteria. It appears, the scientists determined, that darobactin jams the open-close action of the gate-like protein BamA, which gram-negative bacteria need to build their characteristically thick, antibiotic-resistant outer membrane. Without operating BamA, the bacteria cannot build functioning outer envelopes and they die. According to Dr. Lewis, “we have never seen anything remotely similar to that before among antibiotics.”
The scientists conducted a series of experiments in mice to test darobactin’s ability to fight gram-negative bacterial infections. In one, a single dose of darobactin completely protected animals that had been infected with E. coli, K. pneumoniae or another kind of antibiotic-resistant gram-negative bacteria, P. aeruginosa. The compound showed no signs of toxicity in mice.
These early results, published in Nature, are a first step in a long journey from a compound that works in mice to a new antibiotic drug that is safe and effective in people. Nevertheless, the discovery of darobactin and the methods used by Dr. Lewis to investigate potential antibiotics from natural sources hold promise for finding new potential drugs even in the most unlikely of settings.
Reference: Y Imai, et al. A new antibiotic selectively kills Gram-negative pathogens. Nature DOI: 10.1038/s41586-019-1719-1 (2019).