TSRI researchers spotlight a hidden cause of antibiotics resistance

A team at The Scripps Research Institute (TSRI) has characterized a novel set of genes that are "switched on" during drug resistance of the important human pathogen--Staphylococcus aureus.

TSRI's Floyd Romesberg

"This explains why antibiotic resistance rates in some bacteria are higher than in others," said senior author Floyd Romesberg. "Resistance depends on this little set of genes that no one knew could contribute to tolerating the arylomycins."

Antibiotic drug resistance is a major threat to modern healthcare and how we manage treatment in patients that no longer respond to drugs targeting bacterial pathogens. Despite clever ways to optimize antibiotics including arylomycin--previously designed by TSRI--even this shows bacterial resistance.

Arylomycin works by inhibiting a bacterial protein called Type I signal peptidase (SPase), an "essential" protein since scientists believed bacteria could not live without it. SPases clip peptide sequences off proteins during the translocation of proteins to outside of the cell--as such the important proteins accumulate in the cell and the bacterium dies.

This theory was corrected when the Romesberg lab at TSRI showed some bacteria in fact could survive even after deleting the gene necessary to produce SPase.

How S. aureus could survive without SPase was their next objective and they subsequently discovered a group of genes that team up and compensate for the lack of SPase. They found AyrR switches these genes on to produce AyrA and AyrBC which work in a similar peptide-cleaving behaviour to SPase--thought to be an evolutionary conserved mechanism for helping out SPase when the bacterium faces high protein secretion levels.

"We took it for granted that we knew all the steps of protein secretion", said Arryn Craney, who is the first author and a TSRI research associate. "Now we've found a way to bypass SPase."

The next step will be to understand how the AyrA- and AyrBC-producing genes are switched on in the first place—having implications in human cells since protein secretion and trafficking is conserved in all life forms.

- here's the release

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