News / 13 June 2019

Glycopeptide antibiotics (GPA) are an important class of antibiotics, often used as the last resort against resistant bacteria. Vancomycin for example, is used to fight infection by the deadly Staphylococcus aureus (golden staph) bacteria.

Understanding the machinery of GPAs is vital to the quest to tweak them and develop new antibiotics to keep pace with ever-evolving multi drug-resistant ‘superbugs’, identified by the World Health Organization as an increasingly serious threat to global public health.

A study led by EMBL Australia Group Leader Assoc Prof Max Cryle from the Monash Biomedicine Discovery Institute (BDI) has provided new insights into GPA biosynthesis, which its authors say will have great value in redesigning the biosynthetic pathways that underpin the production of these important antibiotics.

The study, published in Nature Communications investigated the biosynthesis of kistamicin, an unusual GPA.

“Kistamicin is an interesting compound because even though it is from the same group of compounds that usually kill bacteria, like vancomycin, it actually has antiviral activity instead,” senior author Assoc Prof Cryle, who is also a member the ARC Centre of Excellence in Advanced Molecular Imaging, said.

“It’s different structurally to other GPAs in that the peptide core of these compounds is crosslinked in different ways,” he said.

“While we knew about the structure previously we didn’t know the details of how kistamicin is biosynthesised.”

The researchers performed a comprehensive analysis of the way kistamicin is naturally produced and found that its unusual structure was underpinned by the activity of two key enzymes not found in typical GPA biosynthesis.

“Glycopeptide antibiotics share the same crosslinking, which is different to that found in kistamicin and is likely responsible for the different activities of these related compounds,” Assoc Prof Cryle said.

“We also found that – despite the differences – the enzymatic systems that make them work in the same way, which means we could in future produce different antibiotics by mixing and matching enzymes from different biosynthetic systems,” he said.

Whilst kistamicin was investigated in this case, the finding may apply to other types of antibiotics even beyond the glycopeptide antibiotics, he said.

The study was a collaboration between the Monash BDI and scientists from the University of Tübingen, Max Planck Institute for Medical Research, University of Queensland and Australian National University.

First author was Dr Anja Greule (pictured above) from Assoc Prof Cryle’s laboratory in the Department of Biochemistry and Molecular Biology.

Read the full paper in Nature Communications titled Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics.

This article was originally published on the Monash BDI website and was republished here with permission.
DOI: 10.1038/s41467-019-10384-w

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