Scientists find sweet spot for tackling resistant pathogen
Australian researchers have designed antibodies able to recognise a sugar present only on bacterial cells.
They employed them to fight successfully one of the six multidrug resistant pathogens responsible for the majority of hospital-acquired infections.
The work published in Nature Chemical Biology could enable development of immunotherapies for bacteria-derived drug resistant infections.
Professors Richard Payne from the University of Sydney and Ethan Goddard-Borger at WEHI and associate professor Nichollas Scott at the University of Melbourne and the Peter Doherty Institute for Infection and Immunity created the laboratory-made antibody.
They described how it removed a lethal bacterial infection, Acinetobacter baumannii, in mice by homing in on the distinctive bacterial sugar molecule pseudaminic acid in order to identify the pathogen for destruction by the immune system.
Together with Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterobacter, Acinetobacter baumannii forms one of the six so-called ESKAPE pathogens significant in hospital infections.
Pseudaminic acid is produced only by bacteria and used by numerous pathogens as components of their outer coats and to evade immune responses. Humans do not produce it.
“This study shows what’s possible when we combine chemical synthesis with biochemistry, immunology, microbiology and infection biology,” Payne said.
“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. That opens the door to new ways of treating some devastating drug-resistant bacterial infections.”
The trio chemically synthesised the bacterial sugar and sugar-decorated peptides to determine the exact three-dimensional arrangement of the molecule and how it is presented on bacterial surfaces.
They then developed a ‘pan-specific’ antibody able to pinpoint the sugar across a wide range of bacterial species and strains.
Acinetobacter baumannii, one cause of hospital-acquired pneumonia and bloodstream infections, was eliminated in mouse models.
“Multidrug resistant Acinetobacter baumannii is a critical threat faced in modern healthcare facilities across the globe,” Goddard-Borger said.
“It is 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 involves administering ready-made antibodies to rapidly control an infection, not waiting for the individual’s adaptive immune system to respond to the infection.
Scott said the antibodies also provided insight for understanding how bacteria cause disease.
“These sugars are central to bacterial virulence, but they’ve been very hard to study. 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.”
Over a five year period, the team will convert their findings into clinic-ready antibody therapies, targeting Acinetobacter baumannii.
Payne said. “Our goal is to turn fundamental molecular insight into real-world solutions that protect the most vulnerable people in our healthcare system.”
Payne will also lead the recently announced Australian Research Council Centre of Excellence for Advanced Peptide and Protein Engineering, which seeks to translate this advance for applications in such areas as biotechnology, agriculture and conservation.
Pic (right, descending order): Richard Payne, Ethan Goddard-Borger and Nichollas Scott
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