Resistance is futile

When antibiotics first became widely used to fight off infections a little more than 100 years ago, they revolutionized medicine. In fact, the average human lifespan has increased by 23 years over the past century, thanks to these drugs. Unfortunately, antibiotic-resistant “superbugs” are on the rise. In the United States alone, there are more than 2.8 million cases of antimicrobial-resistant infections each year, resulting in more than 35,000 deaths, according to the Centers for Disease Control and Prevention.  

We need new strategies for combatting these superbugs, and a collaborative team of researchers, led by UMass Amherst and including scientists from the biopharmaceutical company Microbiotix, is on the job. They’re digging into how these microbes work and how best to defeat them. And a recent breakthrough, published in a paper in the journal ACS Infectious Diseases, means the team may be closer than ever to finding solutions.  

Tiny toxic needles 

The team’s research is focused on understanding how pathogens attack their host on the cellular level. Alejandro P. Heuck, associate professor of biochemistry and molecular biology and the paper’s senior author, explains that some disease-causing pathogens “have developed weapons that are like nanosyringes that inject toxins into our cells.”    

According to Heuck, these toxins can paralyze macrophages—a type of white blood cell that engulfs and digests pathogens—and destroy the layer of cells that provides the first line of defense against invaders, opening the door for bacteria to enter. But by figuring out the inner workings of these nanosyringes (also known as the Type III secretion system), researchers can find ways to inhibit them. Disabling these nanosyringes would prevent even antibiotic-resistant pathogens from evading the body’s natural defenses, significantly decreasing the emergence of new superbugs.    

Based on work done by Yuzhou Tang ’18PhD and published in the Journal of Biological Chemistry, the team started out with the idea of using a reporter—a genetically engineered tag in one of the proteins that make up the nanosyringes—that would allow them to see whether a cell had been injected. Their first idea produced a very weak signal, but fortunately, another bright idea was on the horizon.  

Let there be light  

Another of the graduate students in the lab, Hanling Guo ’25PhD, dug deep into the literature and found an alternative: nanoluciferases—enzymes able to enhance or catalyze a reaction, essentially amplifying the signal. “Instead of just trying to reconstitute a single molecule that generates light, we reconstituted an enzyme that could create hundreds of other molecules that lit up,” says Heuck.  

Tang and Guo’s work led the researchers to add one small part of the nanoluciferase enzyme to the proteins that make up the nanosyringe and engineer the rest of the protein into the target cell. That way, if the nanosyringe successfully penetrates the cell wall, the two halves of the enzyme will come together, and hundreds of molecules will light up.  

Using this approach, the team is working to find a molecule that will act as an inhibitor to these nanosyringes. The researchers are testing thousands of compounds to see which ones block the appearance of light, an indicator that the pathogen has failed to infect the cell. If they can identify a winner, pharmaceutical companies could use that knowledge to develop new medications to reduce the emergence of superbugs.  

Turning the tables 

At the same time, the research team continues to study just how these nanosyringes work. “We still don’t understand how these proteins that go through the syringe of the bacteria and are secreted outside the bacteria enter the membrane of the target cell,” says Heuck. But once his team learns more about the workings of the nanosyringes, they may be able to turn the tables and use these structures for good.  

Heuck’s team is trying to use the nanosyringes to deliver beneficial substances. “Instead of the pathogen using the syringes to inject toxins,” he says, “if we can engineer the pathogen to remove all the toxins and then add proteins that we want to deliver to cells—for example, to kill cancer cells—we can use the needles to our advantage.”