Two Glycopeptide Antibiotics Have Never-Before-Seen Way to Kill Bacteria

Two members of a new class of glycopeptide antibiotics — the previously known glycopeptide antibiotic complestatin and a newly-discovered compound called corbomycin — have a unique mechanism of action against bacteria, according to a paper published in the journal Nature.

TEM image of Bacillus subtilis grown in corbomycin shows a characteristic twisted phenotype; red triangles mark sites of aberrant-division septa formation, thickened cell wall and granular formations. Image credit: Culp et al, doi: 10.1038/s41586-020-1990-9.

TEM image of Bacillus subtilis grown in corbomycin shows a characteristic twisted phenotype; red triangles mark sites of aberrant-division septa formation, thickened cell wall and granular formations. Image credit: Culp et al, doi: 10.1038/s41586-020-1990-9.

In the study, McMaster University Ph.D. candidate Beth Culp and colleagues looked at the family tree of known members of the glycopeptides.

They studied the genes of those lacking known resistance mechanisms, with the idea they might be an antibiotic demonstrating a different way to attack bacteria.

“We hypothesized that if the genes that made these antibiotics were different, maybe the way they killed the bacteria was also different,” Culp explained.

The researchers found that two glycopeptide antibiotics, corbomycin and complestatin, have a never-before-seen way to kill bacteria, which is achieved by blocking the function of the bacterial cell wall.

“Bacteria have a wall around the outside of their cells that gives them shape and is a source of strength,” Culp said.

“Antibiotics like penicillin kill bacteria by preventing building of the wall, but the antibiotics that we found actually work by doing the opposite — they prevent the wall from being broken down. This is critical for cell to divide.”

“In order for a cell to grow, it has to divide and expand. If you completely block the breakdown of the wall, it is like it is trapped in a prison, and can’t expand or grow.”

The scientists confirmed that the bacterial wall was the site of action of these new antibiotics using cell imaging techniques.

“This approach can be applied to other antibiotics and help us discover new ones with different mechanisms of action,” Culp said.

“We found one completely new antibiotic in this study, but since then, we’ve found a few others in the same family that have this same new mechanism.”

The authors also demonstrated in mice that corbomycin and complestatin can block infections caused by methicillin-resistant Staphylococcus aureus (MRSA).

“Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection,” they said.

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E.J. Culp et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature, published online February 12, 2020; doi: 10.1038/s41586-020-1990-9

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