A new antibiotic kills dangerous and resistant bacteria

A new antibiotic kills dangerous and resistant bacteria

A new antibiotic kills dangerous and resistant bacteria

A new antibiotic kills dangerous and resistant bacteria

Research is an important step in the development of new effective drugs.

A new antibiotic that can fight against resistant bacteria.

Antibiotics have long been considered a miracle cure for bacterial infections. However, many pathogens have evolved over time to withstand antibiotics and therefore the search for new drugs is increasingly urgent. Researchers from University of Basel were part of an international team that used computer analysis to identify a new antibiotic and decipher its mode of action. Their research is an important step in the creation of new, powerful medicines.

The WHO calls the ever-increasing number of bacteria that are resistant to antibiotics a “silent pandemic”. The situation is aggravated by the fact that not many new drugs have entered the market in recent decades. Even now, not all infections can be properly treated, and patients are still at risk of injury from routine interventions.

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

Tough opponents

Researchers have discovered a new antibiotic, Dynobactin, using a computational screening approach. This compound kills Gram-negative bacteria, which include many dangerous and resistant pathogens. “The search for antibiotics against this group of bacteria is far from trivial,” says Hiller. “They are well protected by their double membrane and therefore offer little opportunity for attack. And over millions of years of evolution, bacteria have found numerous ways to render antibiotics harmless.”

It was only last year that Hiller’s team deciphered the mode of action of the recently discovered peptide antibiotic Darobactin. The acquired knowledge is integrated into the process of searching for new compounds. The researchers took advantage of the fact that many bacteria produce antibiotic peptides to fight each other. And that these peptides, unlike natural substances, are coded in the bacterial genome.

Fatal effect

“The genes for such peptide antibiotics share a characteristic feature,” explains co-author Dr. Seyed M. Modaresi. “According to this feature, the computer systematically screened the entire genome of those bacteria that produce such peptides. That’s how we identified Dynobactin.” In their study, the authors showed that this new compound is extremely effective. Mice with life-threatening sepsis caused by resistant bacteria survived severe infection with Dynobactin.

By combining different methods, the researchers were able to solve the structure as well as the mechanism of action of Dynobactin. This peptide blocks the bacterial membrane protein BamA, which plays an important role in the formation and maintenance of the outer protective bacterial envelope. “Dynobactin sticks to BamA from the outside like a plug and prevents it from doing its job. So the bacteria die,” says Modaresi. “Although Dynobactin has almost no chemical similarities to the already known Darobactin, it still has the same target on the bacterial surface. We didn’t expect this at the beginning.”

Stimulus for antibiotic research

At the molecular level, however, the scientists found that Dynobactin interacts with BamA differently than Darobactin. By combining certain chemical properties of the two, potential drugs can be further improved and optimized. This is an important step on the way to an effective drug. “Computerized screening will give new impetus to the identification of urgently needed antibiotics,” says Hiller. “In the future, we want to expand our search and investigate more peptides in terms of their suitability as antimicrobial drugs.”

Reference: “Computational Identification of a Systemic Antibiotic for Gram-Negative Bacteria” Ryan D. Miller, Akira Iinishi, Seyed Majed Modaresi, Byung-Kuk Yoo, Thomas D. Curtis, Patrick J. Lariviere, Libang Liang, Sangkeun Son, Samantha Nicolau, Rachel Bargabos, Madeleine Morrissette, Michael F. Gates, Norman Pitt, Roman P. Jakob, Parthasarathi Rath, Timm Maier, Andrey G. Malyutin, Jens T. Kaiser, Samantha Niles, Blake Karavas, Meghan Ghiglieri, Sarah EJ Bowman, Douglas C. Rees, Sebastian Hiller and Kim Lewis Microbiology of nature.
DOI: 10.1038/s41564-022-01227-4


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