Root-knot nematode (Agricultural Research Service, USDA)
22 Nov. 2019. Researchers in the U.S. and Germany discovered a new source of antibiotics to fight drug-resistant bacteria from common worms living in soil. A team from Northeastern University in Boston, Justus Liebig University in Giessen, Germany, and other institutions report their findings in the 20 November issue of the journal Nature (paid subscription required).
In its annual report on antibiotic resistance for 2019, Centers for Disease Control and Prevention says more than 2.8 million of infections from drug-resistant bacteria occur each year in the U.S., leading to more than 35,000 deaths. A particular difficult type of microbe to battle are called gram-negative bacteria. “Gram” refers to a classification for bacteria where the microbes either retain (gram-positive) or shed (gram-negative) a test stain on their protective cell coatings.
The tough coating on gram-negative bacteria causing the microbes to shed the testing stain also helps protect the bacteria from antibiotics. Escherichia coli or E. coli and Klebsiella pneumoniae, often found in health care facilities are examples of gram-negative bacteria.
The microbiology lab led by Kim Lewis at Northeastern studies uncultured bacteria, microbes living naturally and making up the majority of organisms on the planet but not grown in the lab as new sources of antibiotics. The lab looks particularly for protective mechanisms developed by these microbes that can be harnessed for humans. That search led to nematodes, a common parasitic worm living in soil, often used as a model organism in the lab. Nematodes carry a bacterium called Photorhabdus that protects the worms against its natural enemies.
Photorhabdus lives in the nematode’s gut and secretes a peptide, a short chain of amino acids, with a symbiotic relationship that allows it live inside the worm but is still toxic to enemy caterpillars. The researchers call this peptide darobactin, and in their investigation reveal several desirable qualities for human antibiotics. First, it has a unique chemical ring structure making it difficult to build resistance. Second, darobactin binds to a protein on the target bacterial outer cell membrane that disrupts the membrane, making bacterium more susceptible to attack.
The researchers hypothesized darobactin would kill drug-resistant bacteria, but still be non-toxic to mammals. “Since Photorhabdus bacteria live in the nematode, and the nematode is an animal just like we are, whatever they make has to be non-toxic [for us],” says Lewis in a Northeastern statement. “These compounds also have to move through and survive in the tissues of the caterpillar, which is also an animal and is actually very similar to us.”
Tests with lab mice show darobactin cleared infections of antibiotic-resistant strains of E. coli and Klebsiella pneumoniae bacteria in lab mice, with no signs of toxicity to the animals. Further tests show that when a strain of E. coli bacteria developed a resistance to darobactin, that resistance also weakened its outer cell membrane, making E. coli more susceptible to ordinary antibiotics.
Darobactin is still in drug discovery, requiring more testing and refinement before its ready for human clinical trials. Lewis and colleagues at Northeastern founded the company NovoBiotic Pharmaceuticals, LLC in Cambridge, Massachusetts to discover new antibiotics from natural sources. The company received numerous small business set-aside grants over the years supporting its work.
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