An example of a bacterial artist

The research is an important step for the development of new effective drugs.

A new antibiotic to fight resistant bacteria.

Antibiotics are long considered a miracle cure for bacterial infections. However, many pathogens have evolved to resist antibiotics over time, so the need to find new drugs is becoming more urgent. Researchers from University of Basel They were part of an international team that used computational analysis to identify a new antibiotic and unravel its mechanism of action. Their research is an important step in creating new, powerful drugs.

The World Health Organization refers to the growing number of antibiotic-resistant bacteria as a “silent epidemic.” The situation has been exacerbated by the lack of new drugs that have entered the market in recent decades. Even so, not all infections can be properly treated, and patients are still at risk of harm from routine interventions.

New active ingredients are urgently needed to stop the spread of antibiotic-resistant bacteria. A significant discovery was recently made by a team of researchers. Northeastern University in Boston and Professor Sebastian Hiller from the University of Basel Biozentrum. The results of this research, which is part of the “AntiResist” project of the National Center for Research Excellence (NCCR), have been published recently. Nature Microbiology.

Strong opponents

The researchers discovered the new antibiotic dinobactin through a computational screening method. This compound kills gram-negative bacteria, including many virulent and resistant pathogens. “The search for antibiotics against this group of bacteria is far from easy,” says Hiller. “They are well protected by a double layer and therefore offer little opportunity for attack. Over millions of years of evolution, bacteria have found many ways to neutralize antibiotics.

Just last year, Hiller’s group solved the mechanism of action of the recently discovered peptide antibiotic darobactin. The knowledge gained is included in the process of screening for new compounds. The researchers used the fact that many bacteria produce antibiotic peptides to fight each other. And these peptides, unlike natural substances, are stored in the bacterial genome.

Fatal result

“Genes for such peptide antibiotics have characteristic properties,” said co-first author Dr. Syed M. Modaresi said. “Based on this characteristic, the computer systematically screened the entire genome of bacteria that produce these peptides. This is how we identified dinobactin.” In their study, the authors showed that this new compound was extremely effective: mice with life-threatening sepsis survived severe infection with the administration of dinobactin.

By combining different methods, the researchers were able to solve the structure and mechanism of dinobactin. This peptide blocks the bacterial membrane protein BamA, which plays an important role in the formation and maintenance of the outer-protective bacterial envelope. “Dinobactin sticks to the outside of BMA as a plug and prevents it from doing its job. So the bacteria die,” says Modaresi. Although dinobactin has no chemical similarities with the already known Darobactin, it has a similar target on the surface of the bacteria. This was not expected at first.

Encouragement for antibiotic research

At the molecular level, however, scientists discovered that dinobactin interacts with BMA differently than darobactin. By combining some of the chemical properties of the two, potential drugs can be further developed and improved. This is an important step on the way to effective medicine. “Computer-based screening provides a new incentive to identify urgently needed antibiotics,” says Hiller. “In the future, we want to expand our search and investigate the suitability of more peptides as antimicrobial drugs.”

Reference: “Evaluation of Systemic Antibiotics for Gram-Negative Bacteria” by Ryan D. Miller, Akira Einishi, Seyed Majid Modaresi, Byung-Kook Yo, Thomas D. Curtis, Patrick J. Lariviere, Libang Liang, Sangkeun Son, Samantha Nicolau, Rachel Bargabos, Madeleine Morissette, Michael F. Gates, Norman Peet, Roman P. Jacob, Parthasarathy Rath, Tim Mayer, Andre G. Malutin, Jens T. Keyser, Samantha Niles, Blake Karavas, Meghan Ghiglieri, Sarah EJ Bowman, Douglas C. Reese, Sebastian Hiller, and Kim Lewis. Nature Microbiology.
DOI: 10.1038/s41564-022-01227-4

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