Super drugs for superbugs: Creative ways to combat antibiotic resistance

New discoveries could overcome antibiotic development stalemate, stay ahead of bacteria’s steady march toward drug resistance
The iChip, developed at Northeastern University, lets researchers study many new types of bacteria by growing them in their native environment. The research team isolated a potential new antibiotic from a previously undiscovered bacterium buried deep in a field in Maine. Photo by Slava Epstein / Northeastern University

In the ongoing war between bacteria and the drugs to beat them, the stakes keep rising as the bugs evolve to become dominant in a life or death contest of one-upmanship.

Each year, antibiotic-resistant bacteria sicken more than 2 million in the U.S. and kill at least 23,000, according to estimates by the Centers for Disease Control and Prevention. The threat is so high that in September, President Barack Obama signed an executive order calling for action to stem the rise of these “superbugs.”

Antibiotic development has slowed to a crawl in recent decades, but several creative new approaches to fighting superbugs could turn that around, including tricking soil bacteria to grow in the lab and compounds that could halt antibiotic resistance by slowing bacterial evolution.

Last week, a team of scientists led by biochemist Dr. Kim Lewis of Northeastern University announced the discovery of an antibiotic extracted from a previously undiscovered bacterium. In laboratory tests that aimed to replicate bacterial evolution of antibiotic resistance, it showed signs that the drug may prove “largely resistance-free,” as Lewis said in an NPR interview.

The newly discovered compound, teixobactin, has yet to be tested in humans but has the potential to combat antibiotic resistance through its unique way of killing bacteria.

Teixobactin can kill several types of infectious bacteria in petri dishes, including methicillin-resistant Staphylococcus aureus (otherwise known as MRSA) and the bacterium that causes tuberculosis. It also cleared mice of MRSA infections.  

Teixobactin acts by altering the building blocks of some types of bacterial cell walls. The researchers hypothesize that those building blocks are so fundamental that they may not be easily changed by mutation to develop resistance to the drug. For example, it took 30 years for resistance to crop up to the antibiotic vancomycin, which works in a similar way.

Grassy field yields pay dirt

Nearly all classes of antibiotics in use today were derived from naturally occurring compounds – bacteria and fungi make their own powerful antibiotics to compete with other nearby microbes. To find the novel antibiotic, the Northeastern researchers used a special incubation chamber they dubbed the “iChip” to study the many bacteria teeming in the soil that scientists had never before been able to grow in the laboratory.

Lewis and his team were able to trick these bacteria into growing in the lab by seeding the iChip with diluted soil collected from a grassy field in Maine and then burying the chamber back in its own native dirt. After a month, once the bacteria had reached critical mass within tiny divots inside the device, many grew more readily on petri dishes.

“Many microbes like to have family around,” said Dr. Gerald Smith, a microbiologist at Fred Hutchinson Cancer Research Center whose research aims to prevent antibiotic resistance by curbing microbial evolution. “Once they get to a sizeable population, they do well because they help each other.”

Only 1 percent of native soil bacteria will grow in normal laboratory conditions, according to the report in the journal Nature, but the iChip yielded growth of nearly half of the soil bacterial species, giving the researchers thousands of previously uncultured microbes to mine for potential new antibiotics.

“The reason this [approach] is so hopeful is that microbes have been at work in drug development for probably a billion years. Humans have been at it for half a century,” said Smith, who was not involved in the iChip study. “Lewis is taking advantage of the evolution of antibiotics that’s right out there in the world … all we have to do is go find them and exploit them.”

But without new approaches like the iChip, the methods that proved so fruitful in the 1950s and ‘60s heyday of antibiotic discovery eventually stopped working – scientists had exhausted all the antibiotic-producing bacteria that could be grown in the lab.  

The discovery slowdown, combined with drug companies’ increasing reluctance to pursue new antibiotic development due to their low potential for profit, means that very few new antibiotics have made it to market in recent years. Since the 1960s, no new classes of broad-spectrum antibiotics – drugs like penicillin which can kill many different types of bacteria – and only two classes of narrowly acting antibiotics have been discovered.

In recent decades, scientists have overwhelmingly turned to synthetic means of antibiotic discovery. Chemists have created massive collections of artificial compounds, and biologists have sifted through those libraries for molecules that could kill bacteria. That approach showed some utility but not much, Smith said, pointing to the dearth of new antibiotics brought to market since this approach gained popularity.

“None of those molecules that we’ve tested is anywhere near as complicated as the ones that nature makes,” Smith said, with obvious awe for teixobactin’s natural intricacy. “When I looked at the structure of [teixobactin], I said, ‘Holy moley, how is anybody ever going to make that thing?’”

Scientists can certainly synthesize teixobactin in the lab now that they know what it looks like, Smith said. But odds were slim that chemists would ever devise that complex structure on their own without already knowing its potential power.

Dr. Gerald Smith
Dr. Gerald Smith is a microbiologist at Fred Hutchinson Cancer Research Center whose research aims to prevent antibiotic resistance by curbing microbial evolution. Fred Hutch file

Stopping evolution in its tracks

Smith’s approach to antibiotic discovery takes a unique twist on sorting manmade molecules. For the past three decades, he’s been studying how cells repair broken DNA. It turns out that bacteria use a different tool in their kit to repair damaged DNA than humans and other higher organisms do.

That DNA repair kit is often called into action in the course of a pathogen’s life – host immune cells emit DNA-breaking chemicals in defense against infections. Bacteria and other pathogens must quickly and continuously fix their damaged DNA to survive their harsh environs.

Smith noted that nearly all bacterial species use a class of enzymes known as RecBCD for that quick fix, and he and his colleagues later showed that bacteria missing those enzymes can’t infect animals as readily.

Smith joined forces with Fred Hutch microbiologist Dr. Nina Salama, who studies Helicobacter pylori, the bacterium responsible for gastric ulcers and stomach cancer. A few years ago, after screening through a library of 326,000 engineered molecules, the team found several compounds that stop RecBCD from working. And Salama and her team went on to show that some of these compounds can halt Helicobacter infection in mice, with no obvious toxic side effects.

Most excitingly for Smith, RecBCD is also important for bacterial evolution – mutation rates accelerate when DNA is broken, and those mutations lead to the rapid evolution that can eventually drive antibiotic resistance. So these compounds could not only lead to a new class of broad-spectrum antibiotics by blocking repair of broken DNA, but they could also prevent a major route to antibiotic resistance by stopping bacterial evolution in its tracks.

Like teixobactin, these compounds still need to be put through their paces before they’re ready for human use, and still more before their ability to staunch antibiotic resistance is proven. 

Smith originally did not want to get into the drug development game, preferring instead to focus on basic science. But after fruitless attempts to convince drug companies to follow up his ideas regarding RecBCD, Smith decided to take action himself. And now, as funding for the antibiotic project has dwindled, he finds himself questioning whether he’ll continue down this path – but he hopes that the start he made will spur others in the field to follow.

“I decided if I’m going to do something directly useful for humans before I keel over, it was time to start on this.”

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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