From Old Drugs, New Hope

St. Jude scientist redesigns an existing antibiotic to combat drug-resistant infections ranging from tuberculosis to pneumonia.

His ancestors were blacksmiths, pounding pieces of metal into new and useful shapes. Today, Richard Lee, PhD, carries on his family legacy in a fascinating way.

As a scientist at St. Jude Children’s Research Hospital, Lee now forges naturally produced chemicals into potential new drugs. He leads an international research effort that has transformed an old, weak antibiotic into a potential super-killer of drug-resistant infections that pose serious health threats to patients at St. Jude and beyond.

Lee’s projects have used leading-edge technology to change the chemical structure of a 50-year-old antibiotic called spectinomycin and create new, more powerful drugs. These second-generation versions show promise in combating drug-resistant tuberculosis (TB). The new drugs may also wipe out bacteria that cause other dangerous drug-resistant infections.

“I like making things, and I find an intellectual challenge in building molecules to fit into molecular targets. It’s extremely rewarding,” says Lee, who works in the hospital’s Chemical Biology and Therapeutics department.

“Doing chemistry for medical purposes has always been appealing to me,” he adds. “St. Jude is a great place to do this, and I love the mission.”

Worldwide impact

Lee knows his work is linked to the well-being of patients around the world.

TB sickens about 500,000 children and kills 1.4 million people worldwide each year. Meanwhile, drug resistance is rising in common bacterial infections that cause pneumonia, meningitis, middle-ear infections and sepsis. Drug-resistant bacteria sicken 2 million U.S. residents yearly, causing 23,000 deaths.

But although the number of cases caused by drug-resistant bacteria is rising, the number of new drugs in the pipeline to treat these infections has dropped. This poses a challenge to the current standard of medical care.

Cancer therapies often suppress the immune system, leaving many St. Jude patients prone to secondary infections.

“An infection with drug-resistant bacteria can be life threatening to cancer patients and can alter the course of their cancer treatments,” Lee says. “So infection control is a key part of making sure we have the highest survival rates possible.

“We’re in a really bad situation because drug resistance is being spread rapidly by globalization.”

Hard work and a spot of luck

To make their discoveries, Lee and his fellow scientists first created a 3-D, atomic-level model of how spectinomycin binds to ribosomes, which are part of the cell’s machinery needed for protein synthesis. The scientists engineered spectinomycin by adding chemical groups that only bind to the bacterial ribosomes. One version of spectinomycin was effective against drug-resistant strains of TB. That version is known as 1599.

An infection with drug-resistant bacteria can be life threatening to cancer patients… Infection control is a key part of making sure we have the highest survival rates possible.

- Richard Lee, PhD

Lee and his colleagues showed how the structural changes in 1599 prevented TB bacilli from pumping it out of the cell. This resulted in 1599 accumulating to high enough levels in the bacilli to disrupt protein synthesis and trigger cell death.

As precise as the computer-aided process is, “I’m continuously amazed by how lucky we are when we work with modified natural products, as they tend to hit the most effective targets and work well in living systems,” Lee observes. “There’s a lot of serendipity in science, and I think a good scientist takes advantage of serendipity.”

The new versions boast the added benefit of decreased toxicity compared with other protein synthesis inhibitors currently used to treat TB. These inhibitors work differently, making it unlikely to cause some of the serious side effects, such as hearing loss and low blood cell counts, which are associated with current therapies.

Breaking down barriers

Applying knowledge gained from his TB studies, Lee designed a second series of compounds. That research generated spectinomycin compounds that are effective against a broader spectrum of drug-resistant bacteria. They include agents responsible for common childhood upper respiratory tract infections, including infections of the inner ear.

But there are many other hurdles to cross between testing the redesigned compounds in the lab and moving them into the clinic. Lee is focused on preclinical testing of these agents and creating oral versions of the new antibiotics—a process he predicts will take years.

But he’s not fixated on the timeline, just the outcome.

“My job isn’t to develop a drug, although I would love to make a drug,” Lee says. “My job is to advance the options for therapy in the future. We’re breaking down barriers, and we’ve potentially opened up a new class of antibiotic medicines.”

From Promise, Winter, 2016

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