Supervillianous Superbugs, Meet Earth's Mightiest Researchers:

If Loki, the trickster god and supervillain of the “Avengers” franchise, has a counterpart in the microscopic world, it’s probably an antibioticresistant bacterium. Physicians and researchers battling infections across the world today face a tricky, mischievous foe in these superbugs, one who seems to shift before scientists’ eyes and slither past their best defenses.

Due to antibiotic over-prescription and misuse, combined with the simple effects of microbe evolution, bacterial infections today frequently survive drugs that had worked for years, said Alan Gross, a clinical pharmacist at UIC who studies multidrug-resistant organisms.

Now, for example, about 40% of patients with a Staphylococcus aureus infection have the formerly rare resistant strain called MRSA (Methicillin-resistant Staphylococcus aureus), Gross said.

Superbugs Meet Their Match

Take heart, however, citizens! Even as these trickster microbes amass in a grotesque army of supervillanous superbugs, Earth’s Mightiest Heroes (mightiest researchers, anyway) are at headquarters devising a counterattack. Meet two intrepid bug warriors at UIC who have taken up shields and hammers in the fight against these resistant bugs: Scott Franzblau, a professor at the UIC Institute for Tuberculosis Research, and Michael Federle, principal investigator in the UIC lab probing bacterial communication.

“ I see critically ill patients, and they’re infected with bacteria that are resistant to everything. We have no antibiotics left to treat them.”

ALAN GROSS Clinical pharmacist at UIC studying multidrug-resistant organisms

Hammering resistant TB

Sometimes, you just need to clobber your foe with a powerful weapon. Like the mighty Thor, and his trusty hammer, superbug researchers often need a storied, old tool. In the fight against resistant microbes, that weapon is the antibiotic drug.

Resistance, however, means that researchers must invent or discover new versions of that weapon. To do so, the UIC institute employs high-throughput systems for testing thousands of potential anti-TB compounds simultaneously.

UIC’s robotics lab helps, he said, but the real hero is modern microplate technology.

Super-Capacity

“If you have access to a robot, you can use microplates that have 384 wells, in the size of a plate that approximates a petri dish,” Franzblau said. “That allows you to test hundreds of samples, where in the past, that same-size plate would just allow you test a few.”

That capacity is rare, so UIC serves as a resource “for any groups in the world who have compounds they think might be useful for TB,” he said.

Franzblau’s lab also conducts its own searches for new compounds to test, using several different approaches. For example, the institute unearthed undiscovered, TB-active compounds produced by soil and other microorganisms. Compounds from these general types of microbes were long ago tested on other diseases, but never against TB. (A common source of antibiotics, these soil, aquatic and marine bugs produce the compounds, it’s hypothesized, to compete with other microbes.)

“The thing that I realized over 10 years ago was that at the time we were finding antibiotics from the soil, the testing was not done directly on TB,” Franzblau said. “It was only after they found something active against [other] bacteria, that they would turn their attention and say, ‘Might it also kill TB?’”

Zeroing In On TB

Since TB is susceptible to many drugs that don’t affect other bacteria, “that implies that researchers would have missed many compounds produced by these soil bacteria that only kill tuberculosis,” he said.

In this effort, UIC collaborates with Korean researchers who have compiled an extensive collection of such microbes. Among the UIC institute’s other approaches, it also aims at particular molecular targets in the TB bacterium.

Once the researchers find an effective compound, by whichever approach, they can send it on to pharmaceutical companies for clinical testing. This is possible today largely due to support from the nonprofit Global Alliance for TB Drug Development, Franzblau said.

In all of these efforts, TB presents unique challenges, even among resistant organisms. Treating active TB requires multiple drugs from the get-go. Physicians have learned that using just one drug results in relapse, Franzblau said.

“We developed ways to test very large numbers of samples — hundreds, thousands, tens of thousands — against real-virulent tuberculosis.”

SCOTT FRANZBLAU Professor, UIC Institute for Tuberculosis Research

“So in the case where you do have multiple drugresistance…you’re in this bizarre situation, where you don’t just need to find one new drug, you need to find multiple new drugs,” he said.

That makes research into new drugs against resistant TB even more pressing, he added.

“Today, we have TB that is resistant to essentially all of the drugs that are available for the disease,” Franzblau said. “It’s really quite an extraordinary challenge.”

Silencing a Signal

Trusty weapons will always have a place in a hero’s arsenal. A complete team, however, also needs new weapons and recruits. The Avengers have their Vision, an amazingly powerful android who can attack in ways his teammates never could. Researchers at UIC, too, have a creative new “vision” in the fight against superbugs. Instead of targeting some feature of a bacterium itself, to kill the bug dead, Michael Federle, principal investigator in the UIC lab probing bacterial communication, aims to stop the bugs from talking to each other.

To do so, Federle and colleagues study the chemical signals that leach out from one bacterium to another.

The Calls Are Coming From Inside

“We’re trying to understand how these bacteria are using chemical signaling…and how that helps them live in our bodies either asymptomatically or in the pathway to making us sick,” he said.

Such signaling is widespread. Individual bacteria secrete so-called pheromones to influence the behavior of their microbial colleagues. Such microbial communiqués do everything from inducing cell division to facilitating the sharing of DNA between different cells.

The idea of Federle’s research, he said, is to silence those signals that make certain bacteria cause harm. For example, in Staphylococcus aureus, when the bacteria population in a patient rises, the bugs’ signals induce the release of toxins, which cause illness. The method would, in theory, work against bacteria like this, which “99.99% of the time” live in human bodies without causing illness, Federle said.

“The data suggest it’s only when these bacteria are stressed…that they go through genetic programs” that cause sickness, he said. “If we can convince the bacteria that they need to go back to living with us without causing harm, they’re going to remain perfectly fit to live in that kind of a niche,” he said.

Resistance Is Futile

Even better, this nonlethal mode of attack is less likely to inspire resistance, Federle said. When you kill bacteria with antibiotics, the survivors will be resistant, and they will likely come to dominate the bacterial population. However, if you merely disrupt the signals that cause “bad bacterial behavior,” the bugs won’t die, and the resistant ones won’t get a competitive advantage.

“We think that might be a more sustainable method, that would not put a strong selective pressure on them to resist this kind of treatment,” Federle said.

Clinically useable drugs deploying this kind of attack will require more research, however, Federle said. He estimates 10 years until the first such medicines will be ready for clinical use. But creative new approaches like this are essential in the fight against resistant bacteria, Federle said.

“Our field needs to identify new antibiotics for sure. But we’ve already hit the low-hanging fruit,” he said. “We also need to be thinking of alternative ways to deal with how bacteria are causing illnesses.” �