The research team has discovered how to subvert antibiotic-resistant ‘superbugs’

The research team has discovered how to subvert antibiotic-resistant ‘superbugs’

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The type 3 secretion system relies on two proteins, PopB and PopD (red and blue), which form a tunnel in the host cell wall. Credit: UMass Amherst

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The type 3 secretion system relies on two proteins, PopB and PopD (red and blue), which form a tunnel in the host cell wall. Credit: UMass Amherst

Antibiotic-resistant “superbugs,” which can thwart efforts to kill them, represent a pressing public health crisis, and according to the Centers for Disease Control, more than 2.8 million antibiotic-resistant infections occur each year. Researchers around the world are seeking to meet this challenge.

A collaborative team of researchers led by the University of Massachusetts Amherst, and including scientists from the biopharmaceutical company Microbiotix, recently announced that they have successfully learned how to subvert a key piece of machinery that pathogens use to infect host cells, and have developed a test to identify next-generation drugs to target this vulnerable cellular machinery and achieve Real gains in public health.

The typical strategy when treating microbial infections is to eliminate the pathogen with an antibiotic drug, which works by entering the harmful cell and killing it. This is not as easy as it sounds, because any new antibiotic needs to be water-soluble, so that it can travel easily through the bloodstream, and oily, so that it can cross the pathogenic cell’s first line of defense, the cell membrane. Of course, water and oil don’t mix, and it’s difficult to design a drug that contains enough of both properties to be effective.

The difficulty doesn’t stop there either, because disease-causing cells have developed what’s called an “efflux pump,” which can recognize antibiotics and then safely flush them out of the cell, where they can do no harm. If the antibiotic cannot overcome the efflux pump and kill the cell, the pathogen “remembers” the form of that specific antibiotic and develops additional efflux pumps to deal with it efficiently—in effect, it becomes resistant to that specific antibiotic.

One way forward is to find a new antibiotic, or a combination of both, and try to stay one step ahead of antibiotic-resistant germs.

“Or we can change our strategy,” says Alejandro Hueck, associate professor of biochemistry and molecular biology at the University of Massachusetts Amherst and lead author of the study. “I’m a chemist, and I’ve always been very interested in understanding how chemical molecules interact with living organisms. In particular, I’ve focused my research on the molecules that make communication possible between a pathogen and the host cell it wants to invade.”

Hyuk and his colleagues were particularly interested in a communication system called the type 3 secretion system, which so far appears to be a unique evolutionary adaptation for pathogenic microbes.

Like the pathogen cell, host cells also have thick cell walls that are difficult to penetrate. In order to penetrate them, pathogens have developed a syringe-like machine that first secretes two proteins, known as PopD and PopB. Neither PopD nor PopB alone can penetrate the cell wall, but together the two proteins can create a “translocon”—the cellular equivalent of a tunnel through the cell membrane. Once the tunnel is established, the pathogenic cell can inject other proteins that infect the host.

This entire process is called the type 3 secretion system, and none of it works without both PopB and PopD. “If we don’t try to kill the pathogen, there’s no chance for it to develop resistance,” Hyuk says. “We’re just sabotaging its machinery. The pathogen is still alive, it’s ineffective, and the host has time.” “To use their natural defenses to get rid of the pathogen.”

The question then is how to find a molecule that can prevent translocon assembly?

Sometimes, solutions come to scientists in those “lightbulb moments” when everything suddenly makes sense. In this case, it was a lightning bug moment.

Hyuk and his colleagues realized that a class of enzyme called luciferase — similar to the one that causes lightning bugs to glow at night — could be used as a tracer. They split the enzyme in half. Half went into the PopD/PopB proteins, and the other half was designed to become a host cell.

These proteins and engineered hosts can be flooded with various chemical compounds. If the host cell suddenly lights up, it means that PopD/PopB successfully penetrated the cell wall, recombining the two halves of luciferase, causing them to glow. But if the cells remain dark? “Then we know which molecules break down the translocon,” Hyuk says.

Hyuk is quick to point out that his team’s research not only has obvious applications in the world of pharmaceuticals and public health, but it is also advancing our understanding of how microbes infect healthy cells. “We wanted to study how pathogens work, and then suddenly we discovered that our findings could help solve a public health problem,” he says.

This research is published in the journal ACS Infectious Diseases.

more information:
Hanling Guo et al., Cell-based screening to identify type 3 Translocon assembly secretion system in Pseudomonas aeruginosa using split luciferase, ACS Infectious Diseases (2023). doi: 10.1021/acsinfecdis.3c00482

Magazine information:
ACS Infectious Diseases

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