A study has been published looking at the mechanism of action of odilorhabdins — a new class of antibiotics — to combat antibiotic resistance, disclosed Nosopharm, a company dedicated to the R&D of new anti-infective drugs, and the University of Illinois at Chicago (UIC).
Antibiotics
The antibiotic was first identified by Nosopharm and are produced by symbiotic bacteria found in soil-dwelling nematode worms that colonise insects for food. This study, published in Molecular Cell, describes the new antibiotic and how it works, finding that they act on the ribosome — the molecular machine of individual cells that makes the proteins it needs to function — of bacterial cells.
“Novel classes of antibiotics like the odilorhabdins are very difficult to discover, but then very interesting to investigate,” said Maxime Gualtieri, co-founder and chief scientific officer of Nosopharm. “Our research at Nosopharm is focused on the understanding of the pharmacology of this new class, and the elucidation of their mode of action is a part of this work. We accumulated several early evidences that the bacterial translation was the target of the ODLs. At this point, we needed complementary scientific expertise to investigate much more in detail the mechanism of action of the molecules. This was the purpose of our collaboration with the UIC.”
“Like many clinically-useful antibiotics, ODLs work by targeting the ribosome,” added Yury Polikanov, assistant professor of biological sciences in the UIC College of Liberal Arts and Sciences. “But ODLs are unique because they bind to a place on the ribosome that has never been used by other known antibiotics.”
“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,” explained Alexander Mankin, director of the Center for Biomolecular Sciences in the UIC College of Pharmacy. “This miscoding corrupts the cell with flawed proteins and causes the bacterial cell to die.
“The bactericidal mechanism of ODLs and the fact that they bind to a site on the ribosome not exploited by any known antibiotic are very strong indicators that ODLs have the potential to treat infections that are unresponsive to other antibiotics.”
“We found that the ODL compounds cured mice infected with several pathogenic bacteria and demonstrated activity against both Gram-negative and Gram-positive pathogens, notably including carbapenem-resistant Enterobacteriacae,” said co-corresponding author Maxime Gualtieri, co-founder and chief scientific officer of Nosopharm.
Carbapenem-resistant Enterobacteriacae (CRE) are a family of germs that are highly resistant to antibiotics. One study suggests that CRE contribute to mortality in up to 50% of patients who become infected.
The first clinical candidate of the odilhorhabdins, NOSO-502, is the most advanced molecule in the company’s portfolio, and it is anticipated to be evaluated in the first clinical trials in humans in 2020.