Scientists uncover a 'bypass' that allows bacteria to resist antibiotics

Scientists have discovered an unknown bypass that Staphylococcus aureus uses to develop resistance to a particular antibiotic. By using this bypass—a previously uncharacterized set of genes—the pathogen can overcome a known method scientists had used to combat resistance. The research was published August 18, 2015 in the journal mBio.

“This explains why antibiotic resistance rates in some bacteria are higher than in others,” said senior author Floyd Romesberg, PhD, Professor at The Scripps Research Institute (TSRI) in La Jolla, CA. “Resistance depends on this little set of genes that no one knew could contribute to tolerating the arylomycins.”

Arylomycin antibiotics usually stop bacterial growth by inhibiting Type I signal peptidase (SPase), long known as an “essential” protein because scientists believed bacteria could not live without it. SPase clips peptide sequences off proteins as the proteins pass from the inside of a cell to the outside. Without this cleaving of the peptides, these proteins cannot reach the outside of the cell and instead accumulate in the membrane, and the bacterium dies.

But, to the researchers’ surprise, they found that S. aureus could survive even after they deleted the gene that produces SPase.

“We did not believe it,” Dr. Romesberg said. “No one would have believed SPase was not essential. If you take the wheels off a car—it’s not going to drive.”

To figure out how S. aureus survived without SPase, the team used DNA sequencing technology to identify a group of genes that work together to fill in for SPase. They found that, in the absence of SPase, a protein called AyrR switches these genes on to produce the proteins AyrA and AyrBC, which can also cleave off the peptide sequences. The scientists believe this workaround may have evolved to help bacteria at times when protein secretion levels are high and SPase couldn’t do the job alone.

“We took it for granted that we knew all the steps of protein secretion,” said Arryn Craney, PhD, a TSRI research associate and first author of the study. “Now we’ve found a way to bypass SPase.”

This discovery shows the built-in redundancies that help bacteria survive in many environments, Dr. Romesberg said. The next step is to figure out how the AyrA- and AyrBC-producing genes are switched on in the first place.

“Trafficking proteins through a cell is also very important for human cells,” Dr. Romesberg said. “All forms of life have to secrete proteins, so discovering this new step in protein secretion has important implications.”