As the incidence of drug-resistant bacteria increase, so does the number of emergency room visits, hospitalizations and deaths.
How are bacteria able to evolve so quickly “Life finds a way,” Singleton says.
The synergy between antibiotic and RecA inhibitor kills E. coli. The black line shows how bacteria multiply in a test tube, growing from 100,000 to approximately 100 trillion in eight hours. Combining RecA inhibitor and ciproflaxin nearly wipes out the E. coli: only one in a million survive.
In his research, Scott Singleton has boosted the bacteria-killing power of several antibiotics. Singleton points to an antibiotic E-test strip in a dish growing E. coli bacteria in his lab at UNC-Chapel Hill's Eshelman School of Pharmacy.
Singleton and research specialist Demet A. Guntas prepare 96 different RecA inhibitors for testing against live bacteria in his lab at the Eshelman School of Pharmacy at UNC-Chapel Hill.

Bacteria bully

When it comes to harmful bacteria, Scott Singleton does not fight fair.

After all, more than 2 million patients each year contract bacterial infections in U.S. hospitals – and 90,000 of those patients die as a result. That’s because in 70 percent of cases, doctors’ best weapon – the antibiotic – does not work. These lethal bugs have developed a resistance to the drugs that once killed them.

Singleton figured out a way to fix the fight.

“Antibiotics versus bacteria is a one-on-one fight, and bacteria are getting bigger and stronger,” says Singleton, an associate professor in the medicinal chemistry and natural products division of the Eshelman School of Pharmacy. “Adding a RecA inhibitor makes it two on one. The inhibitor holds the bacterium down while the antibiotic beats it up.”

Singleton didn’t set out to bully bacteria. But his purely academic interest in how bacteria become resistant to antibiotics so quickly led him to discover something singular about bacterial evolution.

“They don’t wait on luck,” he says. He found that bacteria evolve much more quickly when under stress. The stress sped up the bacteria’s metabolism and triggered an emergency response in certain enzymes that protect and repair the organism’s DNA.

DNA damage caused by antibiotics enables those drugs to kill disease-causing bacteria. But because antibiotics are a major stress for bacteria, the drugs actually trigger the process that speeds up their evolutionary resistance.

The enzyme RecA controls the emergency response and repairs DNA damage caused by antibiotics. “It’s astounding the diversity of roles played by RecA,” Singleton says. “It’s like an employee for a small, regional airline who does every job in the airport: taking your ticket, loading your luggage, and serving drinks.”

Singleton figured that if bacteria can switch on RecA to protect themselves, then chemists should be able to switch it off. Once disabled, RecA no longer defends against an attack and the antibiotic has a better chance of killing the bacteria.

“If we can inhibit RecA, we can make the bacteria much more sensitive to an antibiotic,” Singleton says. “Perhaps more importantly, we can suppress bacteria’s ability to develop resistance to drugs.”

Creating an antibiotic can take a decade or more to develop. Only about three have been introduced in the past 40 years. But Singleton is not creating antibiotics. Instead, his work with RecA inhibitors makes established antibiotics more effective. That means he has been able to attract interest from pharmaceutical companies quickly, even during the recession.

To partner with companies to develop new antibiotic compounds and bring them to market, Singleton started Synereca Pharmaceuticals in 2009. He is president and chief scientific officer.

In March 2010, Synereca became the first UNC research spinoff company to use the Carolina Express License. Carolina Express is designed to make starting a company based on technology invented at UNC easier and faster. It offers a standard set of terms to cover divergent deals with minimal negotiation. The company also won a competitive Small Business Research Loan from the North Carolina Biotechnology Center, a state-funded nonprofit dedicated to developing North Carolina’s biotechnology industry.

Resources and funding from the Carolina KickStart program also boosted Synerec. KickStart is part of the North Carolina Translational and Clinical Sciences Institute at UNC.

“Synereca is off to a great start thanks to entrepreneurship empowered by the University and the strong support of the local RTP community,” Singleton says. “We look forward to re-arming antibiotics to help save lives.

Bacteria bully

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