A new strategy to combat drug-resistant bacteria, engineered by researchers in Australia, offers a promising avenue for developing immunotherapies against infections that are increasingly resistant to antibiotics. The approach centers on targeting a unique sugar molecule found only on the surface of bacterial cells, effectively flagging them for destruction by the immune system.
The research, published in Nature Chemical Biology, demonstrated the successful elimination of a normally fatal bacterial infection in mice using a laboratory-created antibody. This antibody binds to the distinctive bacterial sugar, alerting the body’s natural defenses to attack and eliminate the pathogen. The findings represent a significant step forward in the fight against antimicrobial resistance, a growing global health threat.
Why Target a Bacterial Sugar?
The key to this innovative approach lies in the identification of pseudaminic acid, a sugar molecule present exclusively on bacterial cells. While structurally similar to sugars found in human cells, its exclusive bacterial presence makes it an ideal target for therapies designed to spare healthy tissue. Many dangerous pathogens utilize this sugar as a component of their outer surface, aiding in survival and immune evasion.
“By precisely building these bacterial sugars in the lab with synthetic chemistry, we were able to understand their shape at the molecular level and develop antibodies that bind them with high specificity,” explained Professor Richard Payne of the University of Sydney, who co-led the project with Professor Ethan Goddard-Borger at WEHI and Associate Professor Nichollas Scott from the University of Melbourne and the Peter Doherty Institute for Infection and Immunity. “That opens the door to new ways of treating some devastating drug-resistant bacterial infections.”
A ‘Pan-Specific’ Antibody for Broad Protection
The research team didn’t simply target one strain of bacteria. They first synthesized the bacterial sugar and sugar-decorated peptides from scratch, allowing them to meticulously map its three-dimensional structure and how it presents itself on bacterial surfaces. This detailed understanding enabled the creation of a “pan-specific” antibody – one capable of recognizing the same sugar across a wide range of bacterial species and strains.
This broad-spectrum capability was demonstrated in mouse studies where the antibody effectively cleared infections caused by multidrug-resistant Acinetobacter baumannii. This bacterium is a notorious cause of hospital-acquired pneumonia and bloodstream infections, and is particularly challenging to treat due to its high level of antibiotic resistance.
“Multidrug resistant Acinetobacter baumannii is a critical threat faced in modern healthcare facilities across the globe,” stated Professor Goddard-Borger. “It’s not uncommon for infections to resist even last-line antibiotics. Our work serves as a powerful proof-of-concept experiment that opens the door to the development of new life-saving passive immunotherapies.”
Passive Immunotherapy: A New Approach to Infection Control
The researchers are exploring the use of passive immunotherapy, a treatment strategy that involves administering pre-made antibodies to patients to quickly combat infection, rather than relying on the body’s own immune system to develop a response. This approach can be used both to treat existing infections and to proactively protect individuals at high risk.
In a hospital setting, passive immunotherapy could be particularly valuable for safeguarding vulnerable patients in intensive care units who are susceptible to drug-resistant bacterial infections. The antibodies also offer a novel tool for studying bacterial virulence – how bacteria cause disease.
“These sugars are central to bacterial virulence, but they’ve been very hard to study,” noted Associate Professor Scott. “Having antibodies that can selectively recognise them lets us map where they appear and how they change across different pathogens. That knowledge feeds directly into better diagnostics and therapies.”
From Lab to Clinic: The Next Five Years
The research team is now focused on translating these laboratory findings into clinical antibody treatments, with an initial focus on multidrug-resistant A. Baumannii. Success in this endeavor could significantly reduce the burden of this dangerous pathogen and represent a major advancement in the global fight against antimicrobial resistance.
Professor Payne, who is also set to lead the newly announced Australian Research Council Centre of Excellence for Advanced Peptide and Protein Engineering, emphasized the importance of this work. “This represents exactly the kind of breakthrough the new ARC Centre of Excellence is designed to enable,” he said. “Our goal is to turn fundamental molecular insight into real-world solutions that protect the most vulnerable people in our healthcare system.”
The study received funding from the National Health and Medical Research Council, the Australian Research Council, the National Institutes of Health, the Walter and Eliza Hall Institute of Medical Research, and the Victorian State Government. Researchers also acknowledged support from the Melbourne Mass Spectrometry and Proteomics Facility at the Bio21 Molecular Science and Biotechnology Institute.
All animal handling and procedures were conducted in compliance with the University of Melbourne guidelines and approved by the University of Melbourne Animal Ethics Committee (application ID 29017).
