Soil-dwelling nematodes employ an innovative survival mechanism that has inspired the creation of an entirely new class of antibiotics. They’re called odilorhabdins (ODLs), and early insight into how they work indicates they hold promise for treating antibiotic-resistant infections.
French startup Nosopharm teamed up with researchers from the University of Illinois at Chicago to study natural antibiotics made by nematode worms and develop compounds based on them. Nematodes colonize insects as a food source, producing bacteria to kill their prey. The worms also produce antibiotics to fend off competing bacteria. The Nosopharm team screened 80 strains of nematode-produced bacteria, isolated the most potent antibacterial compounds, and then engineered their own versions of them to increase their potency.
The University of Illinois researchers discovered that the ODLs are similar to other antibiotics in that they target the ribosome, the part of the bacterial cell that makes proteins essential to survival. But ODLs bind to an area of the ribosome that no other antibiotic reaches, and in so doing they disrupt bacteria's ability to translate genetic code.
"When ODLs are introduced to the bacterial cells, they impact the reading ability of the ribosome and cause the ribosome to make mistakes when it creates new proteins," said Alexander Mankin, director of the Center for Biomolecular Sciences in the UIC College of Pharmacy, in a statement. "This miscoding corrupts the cell with flawed proteins and causes the bacterial cell to die."
Nosopharm tested the ODLs it developed against several strains of antibiotic-resistant bugs, including carbapenem-resistant Enterobacteriacae, a common cause of dangerous blood and surgical-site infections. In mice, the compounds cured some infections and demonstrated activity against both gram-positive and gram-negative bugs, the research team reported in the journal Molecular Cell.
The search for new methods of attacking drug-resistant bacterial infections has drawn interest from a wide range of biotech innovators and investors. Just last month, researchers at Roche unit Genentech said they developed an antibody that can cripple gram-negative bacteria by targeting an enzyme on the bugs’ membrane. Startup Macrolide Pharmaceuticals, which was founded on a technology developed at Harvard, is developing antibiotics that bind to ribosomes and block protein synthesis in bacteria. Earlier this month, Novartis veteran Mahesh Karande joined Macrolide as CEO.
Nosopharm has raised more than $5 million in funding since it was founded in 2009. It hopes to bring its most advanced ODL, NOSO-502, into clinical trials in 2020.