Structure of A. baylyi LptB2FG with zosurabalpin (blue) and LPS (grey) bound
A new antibiotic discovered by scientists at Hoffman-La Roche Pharma has the potential to fight drug-resistant infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). CRAB causes serious conditions such as sepsis and pneumonia killing up to 50% of infected patients. The World Health Organisation classify CRAB as a ‘Priority 1’ pathogen due to the critical need for new treatments against this pathogen.
Research published in Nature identified a novel structural class of antibiotics with very potent activity against CRAB strains. The lead molecule, known as zosurabalpin, is a macrocyclic peptide (MCP) and originated from high-throughput screening. After identifying an initial hit compound capable of inhibiting Acinetobacter baumannii, researchers made further modifications to optimise the activity and safety profile of the antibiotic class for use in humans.
Collaborators at Harvard University undertook further studies to understand zosurabalpin’s mechanism of action, showing that the drug inhibits lipopolysaccharide (LPS) transport across the bacterial cell wall by targeting the protein complex involved. Researchers identified that the protein target of zosurabalpin is LptF, a protein which has not previously been targeted by exisiting antibiotics, suggesting existing antimicrobial resistance mechanisms should not affect this drug.
The structural studies undertaken as part of this work highlights both the binding and mechanism of action of zosurabalpin, demonstrating how invaluable the structural biology of multi-protein complexes is for the development of novel pharmaceuticals. Clinical trials for zolsurabalpin will increase understanding for the further development of MCPs as antibiotics.
Antibiotics which target and inhibit a single bacterial protein are more likely to have resistance develop against them, as even a single mutation in the protein can render the drug ineffective. This is an important consideration for future work to develop zosurabalpin and other drugs which target this protein complex.
There is an urgent unmet clinical need to develop new antibiotics against priority pathogens such as CRAB where antimicrobial resistance is a major concern. Developing new antibiotics, and in particular those which hit new targets in the bacterium, is very challenging, and the Zosurabalpin work by teams at Roche and Harvard University is an exciting development for the field.
Zosurabalpin is a narrow spectrum antibiotic, acting specifically on A. baumannii, and does not target other bacteria and minimally interferes with the gut microbiome which is typically affected with broad-spectrum antibiotics. Although only in initial stages of clinical trials, zosurabalpin may provide a route to the development of new drugs to combat A. baumannii infections. It will be interesting to see how zosurabalpin holds up when resistance starts to emerge.
You can read the papers published in Nature here: