This research is an important step in the development of effective new drugs.
A new antibiotic that can fight resistant bacteria.
Antibiotics have long been considered a miracle cure for bacterial infections. has becomeresearchers from University of Basel They were part of an international team that used computer analysis to identify a new antibiotic and decipher its mechanism of action. Their research is an important step towards creating powerful new drugs.
The WHO calls the steady increase in the number of bacteria resistant to antibiotics a “silent pandemic.” The situation is exacerbated by the fact that not many new drugs have been introduced to the market in recent decades. Even now, not all infections can be treated adequately and patients are still at risk of harm from routine interventions.
New active agents are urgently needed to stop the spread of antibiotic-resistant bacteria. An important discovery was recently made by a team led by US researchers. Northeastern University Prof. Sebastian Hiller, Boston, and Prof., Biozentrum, University of Basel. The results of this study, which was a component of the National Center for Research Competence (NCCR) “AntiResist” project, recently natural microbiology.
tough opponent
Researchers discovered a new antibiotic, Dynobactin, through a computational screening approach. This compound kills Gram-negative bacteria, including 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 membranes, so they have little chance of attack. Over millions of years of evolution, bacteria have found many ways to render antibiotics harmless.”
Last year, Hiller’s team deciphered the mechanism of action of the recently discovered peptide antibiotic darobactin. The knowledge gained was integrated into the new compound screening process. Researchers took advantage of the fact that many bacteria produce antibiotic peptides to fight each other. And these peptides are encoded in the bacterial genome, as opposed to natural substances.
deadly effect
“The genes of such peptide antibiotics share distinctive features,” explains co-first author Dr. Seyed M. Modaresi. “According to this characteristic, a computer systematically screened the entire genome of bacteria that produce such peptides. That’s how we identified dynovactin.” demonstrated to be highly effective. Mice with life-threatening sepsis caused by resistant bacteria survived severe infection with administration of dynovactin.
A combination of different methods allowed researchers to elucidate the structure and mechanism of action of dynovactin. This peptide blocks the bacterial membrane protein BamA, which plays an important role in the formation and maintenance of the protective outer bacterial envelope. “Dynobactin attaches to BamA from the outside, like a plug, and prevents it from working, so the bacteria die,” Modaresi says. “Dynobactins have few chemical similarities to the already known darobactins, but they have the same targets on the bacterial surface, which we did not initially expect.”
Boosting antibiotic research
At the molecular level, however, scientists have discovered that dynovactin interacts with BamA in a different way than darobactin. By combining two specific chemical features, potential pharmaceuticals can be further improved and optimized. This is an important step in developing effective drugs. “Computer-based screening will give us another boost in identifying urgently needed antibiotics,” says Hiller. “In the future, we hope to broaden our search to investigate more peptides for their suitability as antimicrobial agents.”
References: 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, Kim Lewis, 2022 September 26th, natural microbiology.
DOI: 10.1038/s41564-022-01227-4
