A Microbial Villain’s Secret Escape

Staphylococcus aureus has a secret mechanism to allow its evil proteins to escape antibiotic blockades

It’s a common staple at the end of many action and police thrillers. Just when it looks like the evil organization is doomed to be destroyed and the villains are surrounded, they reveal some secret tunnel, car, or helicopter to make their escape. The heroes are left scratching their heads as the antagonists head off to demonize another day.

A similar event occurs with the bacterium Staphylococcus aureus. This opportunistic pathogen is responsible for a number of infections ranging from skin irritations to pneumonia and the potentially lethal toxic shock syndrome. Apart from the clinical concern, several isolates also have the ability to resist a number of antibiotics such as penicillin, methicillin (MRSA), and arylomycin.

The action of resistance to each antibiotic varies but in the case of arlomycin, the actual route to resistance has been for the most part a mystery. That changed this past week when a group of American researchers unveiled the mechanism behind this bacterium’s ability to ward off an antibiotic attack. The process involves a newly identified group of genes that help the bacterium continue to survive and maintain its threat to health. Together, these genes provide a secret escape to a variety of proteins many of which are known to cause symptoms and disease.

Before this study had been initiated, the team had already learned about a critical function in arlomycin resistance. At the molecular level, the antibiotic blocks certain proteins such as toxins and immune stimulating proteins from being secreted from the cell. In order for them to leave the cell membrane, they need to be cleaved with an enzyme called type I signal peptidase, also called SPase. The antibiotic prevents SPase from working properly effectively keeping the bad guys caged.

When resistance to the antibiotic occurred, these molecules managed to escape using some secret pathway. When the team looked further into the genetic code, they found a group of four genes worked together to enable this shunt pathway. At the time, they were unsure of their relatedness and so simply called them SA0337 to SA0340.
In last week’s study, the focus was on those four proteins. The team wanted to learn more about them and how they managed to help the evil molecules escape the blockade. After both genetic and protein analysis, the team found the four were working in concert with one another in an operational way. In microbial terms, this is an operon, which they called ayrRABC (arylomycin resistance R, A, B, and C).

Looking closer at the proteins encoded by these genes, the group found R was a repressor that could determine if the other three proteins needed to be expressed. The A, B, and C proteins were the secret getaway henchmen. They created a new secret door allowing the molecules to flow freely outside of the cell.

With the operon characterized, the next step was to determine exactly how arylomycin caused it to be initiated. The answer it turns out was due to SPase. When the enzyme was functioning normally, the R protein keeps the A, B, and C from being expressed. But, if it was blocked, repressed, or deleted, the signal changed allowing the henchmen to be expressed. Soon, the new exit is made and the cell acts as if nothing bad has happened.

But there was some good news to this study. Although the operon was active against arylomycin, there was no activity in the presence of a number of other antibiotics such as vancomycin, trimethoprim, and tetracycline. This suggested complementary therapy using two antibiotics could effectively get past the resistance and eventually clear any infection.

Despite the small good news segment, this article offers a warning to public health officials as this reveals poor prescribing could lead to a lack of success and even more trouble for the patient. A more structured diagnosis and targeted prescriptions is absolutely necessary to minimize the effects of infection.

The article also offers a note of concern for those looking to develop newer antibiotics based on older models. As the authors point out, there are now four families of arylomycin. They may have all contributed to the development of this widespread resistance. In addition, although not tested, any SPase inhibitor may fall victim to the secret escape operon. This underscores the need to properly understanding the mechanism of resistance before heading to the lab bench. If not, much like those police heroes, the efforts to catch and destroy the villainous empire may end up being all for naught.