Potent plant toxins with unique ways to kill harmful bacteria have emerged as one of the most powerful new antibiotic candidates in decades.
An antibiotic called albicidin is produced by a bacterial plant pathogen Xanthomonas albilinean, This causes devastating leaf scorch on sugar cane. Albicidin is thought to be used by pathogens to attack plants and allow their spread.It has been known for some time that albicidin is highly effective in killing bacteria. Escherichia coli When Staphylococcus aureusThese superbugs are notorious for developing resistance to existing antibiotics, increasing the need for effective new drugs.
Despite its antibiotic potential and low toxicity in preclinical studies, drug development of albicidin has been hampered. This is because scientists didn’t know exactly how albicidin interacts with its target, the bacterial enzyme DNA gyrase (gyrase). This enzyme binds to DNA and a series of graceful movements twists it (a process called supercoiling). This is a critical process for proper cell functioning.
Dr. Dmitry Ghilarov’s research group at the John Innes Center is now taking advantage of advances in cryo-electron microscopy, together with the labs of Prof. Roderich Süssmuth at the Technical University of Berlin (Germany) and Prof. Jonathan Heddle at the Jagiellonian University in Poland to develop the first A snapshot of albicidin bound to the gyrase of .
We showed that albicidin can form an L-shape and interact with both gyrase and DNA in a unique way. In this state, the gyrase is no longer able to move and join DNA ends. The effect of albicidin is like throwing a spanner between two gears.
The way albicidin interacts with gyrase is sufficiently different from existing antibiotics that the molecule and its derivatives are likely to be effective against many of the current antibiotic-resistant strains.
“Because of the nature of the interaction, albicidin targets a really important part of the enzyme, and it seems difficult for bacteria to evolve resistance to it,” Dr. Guilaroff said. We can further exploit this binding pocket and further modify albicidin to improve its potency and pharmacological properties.”
This work has already begun. The team used their observations to chemically synthesize antibiotic variants with improved properties. In testing, these variants were effective against some of the most dangerous nosocomial infections, including: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa When Salmonella typhimurium.
Dr. Ghilarov said: It is highly effective at low concentrations and is also highly potent against pathogens that are resistant to widely used antibiotics such as fluoroquinolones. ”
“This molecule has been around for decades,” continues Dr. Ghilarov. Being the first to see how a molecule binds to its target and how it works is a great privilege and one of the greatest rewards of being a scientist. But the work was a big team effort and would not have been possible without our European colleagues. ”
The next step for this research is to work with collaborators in academia and industry to seek funding to advance the research into human clinical trials. This could lead to the development of urgently needed new classes of antibiotics in the face of the global threat of antimicrobial-resistant AMR.
Read the paper: “Molecular mechanisms of topoisomerase poisoning by potent peptide antibiotics” natural catalysishttps://www.nature.com/articles/s41929-022-00904-1
Albicidin – how does it work?
Albicidin targets enzymes found in both plants and bacteria called DNA gyrase (or simply “gyrase”). This enzyme binds to DNA and twists it through a series of graceful movements (a process known as supercoiling). This is a critical process for proper cell functioning. However, Gyrace has an Achilles heel. To do its job, it must momentarily break the DNA double helix. This is dangerous because broken DNA is lethal to cells. Normally, while gyrase works, he quickly rejoins the two DNA fragments, but albicidin prevents the binding, resulting in DNA breakage and the death of the bacterium.
About Antimicrobial Resistance (AMR)
multidrug-resistant pathogens such as Escherichia coli, Pseudomonas aeruginosa When Salmonella typhimurium Presents a dangerous healthcare burden exacerbated by the COVID-19 pandemic.
Infections with resistant pathogens are the leading cause of death in hospital intensive care units, and some strains become bread resistant. Gram-negative drug-resistant pathogens were responsible for 50,000 deaths in 2019.
Despite the urgent need for new drugs to combat this threat, drug discovery programs have not produced a new class of antibiotics for decades.
Original: Sweet Remedy – How Sugarcane Pathogens Are Preparing for a New Era of Antibiotic Discovery
Than: John Innes Center | Technical University of Berlin | Jagiellonian University
