Odilorhabdins: Researchers Discover New Class of Antibiotics

An international team of scientists led by the University of Illinois, Chicago, has discovered a new class of naturally produced, ribosome-targeting antibacterial agents, odilorhabdins, produced by a nematode-symbiotic bacterium.

Thin section of a Xenorhabdus nematophila cell, showing outer membrane blebs on the surface of the cell and in the surrounding area. Image credit: Mattia2 / Kenyon College.

Odilorhabdins are produced by a symbiotic bacterium found in soil-dwelling nematode worms.

Called Xenorhabdus nematophila, the bacterial symbiont produces toxins and immuno-modulators, enabling the nematode to colonize and kill insects. The bacteria further benefit the host nematode by releasing antibiotics that prevent the invasion of the insect’s carcass by other competing bacteria and fungi.

To identify the antibiotics, University of Illinois scientists and their colleagues from Nosopharm, a biotechnology company based in Lyon, France, screened 80 cultured strains of the bacteria for antimicrobial activity.

The researchers then isolated the active compounds, studied their chemical structures and engineered more potent derivatives.

They found that odilorhabdins act on the ribosome — the molecular machine of individual cells that makes the proteins it needs to function — of bacterial cells.

“Like many clinically useful antibiotics, odilorhabdins work by targeting the ribosome. But they are unique because they bind to a place on the ribosome that has never been used by other known antibiotics,” said co-lead author Dr. Yury Polikanov, from the College of Liberal Arts and Sciences at the University of Illinois, Chicago.

The team also found that when bound to the ribosome, odilorhabdins disrupt their ability to interpret and translate genetic code.

Chemical structures of odilorhabdins and the organization of the biosynthetic gene cluster in the odilorhabdin producer: (A) chemical structures of natural odilorhabdins NOSO-95A, B, and C and the structure of the gene cluster in the Xenorhabdus nematophila genome encoding NRPS (non-ribosomal peptide synthetase) proteins responsible for odilorhabdin biosynthesis. The predicted NRPS modules (m1–m10), each composed of a condensation domain (C), an adenylation domain (A), and a thiolation/peptide carrier domain (T), are indicated alongside the amino acids incorporated by the respective modules. X indicates a module whose specificity was difficult to assign on the basis of in silico analysis. Chemical moieties of natural odilorhabdins that are absent or altered in the synthetic NOSO-95179 compound are highlighted in light blue. (B) chemical structure of the fully synthetic odilorhabdin derivative NOSO-95179. Image credit: Pantel et al, doi: 10.1016/j.molcel.2018.03.001.

Chemical structures of odilorhabdins and the organization of the biosynthetic gene cluster in the odilorhabdin producer: (A) chemical structures of natural odilorhabdins NOSO-95A, B, and C and the structure of the gene cluster in the Xenorhabdus nematophila genome encoding NRPS (non-ribosomal peptide synthetase) proteins responsible for odilorhabdin biosynthesis. The predicted NRPS modules (m1–m10), each composed of a condensation domain (C), an adenylation domain (A), and a thiolation/peptide carrier domain (T), are indicated alongside the amino acids incorporated by the respective modules. X indicates a module whose specificity was difficult to assign on the basis of in silicoanalysis. Chemical moieties of natural odilorhabdins that are absent or altered in the synthetic NOSO-95179 compound are highlighted in light blue. (B) chemical structure of the fully synthetic odilorhabdin derivative NOSO-95179. Image credit: Pantel et al, doi: 10.1016/j.molcel.2018.03.001.

“When odilorhabdins 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 co-lead author Professor Alexander Mankin, director of the Center for Biomolecular Sciences in the College of Pharmacy at the University of Illinois, Chicago.

“This miscoding corrupts the cell with flawed proteins and causes the bacterial cell to die.”

“While many antibiotics can slow bacterial growth, antibiotics that actually kill bacteria, called bactericidal antibiotics, are rare.”

“The bactericidal mechanism of odilorhabdins and the fact that they bind to a site on the ribosome not exploited by any known antibiotic are very strong indicators that odilorhabdins have the potential to treat infections that are unresponsive to other antibiotics,” Professor Mankin said.

The team’s members at Nosopharm tested the odilorhabdin compounds against bacterial pathogens, including many known to develop resistance.

“We found that the odilorhabdin compounds cured mice infected with several pathogenic bacteria and demonstrated activity against both Gram-negative and -positive pathogens, notably including carbapenem-resistant Enterobacteriacae,” said co-lead author Dr. Maxime Gualtieri, co-founder and chief scientific officer of Nosopharm.

The findings appear in the journal Molecular Cell.

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Lucile Pantel et al. Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site. Molecular Cell, published online April 5, 2018; doi: 10.1016/j.molcel.2018.03.001

Source: sci-news.com

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