Story URL: http://news.medill.northwestern.edu/chicago/news.aspx?id=228063
Story Retrieval Date: 10/30/2014 11:53:08 PM CST

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St Jude's Children's Research Hospital

Richard Lee and his colleagues are researching a new class of mutant drugs to combat resistant tuberculosis.


Spectinamides: New class of mutant drugs makes progress against TB

by Mary Stutzman
Feb 14, 2014


Anne Lenaerts had pursued cancer research in her native Belgium, when she got a chance to travel to Africa.

There she witnessed and worked with tuberculosis patients for the first time—and couldn’t get it out of her system.

She ended up living in South Africa for two and a half years.

“When I saw firsthand what a cruel disease this is, the mortality rate…I wanted to continue to work on TB,” she said. That’s exactly what she’s done.

Lenaerts, now a professor of microbiology at Colorado State University, is one of the collaborating scientists in a recent study developing spectinomides, a new class of antibiotics that could be effective against multidrug-resistant tuberculosis, a global illness on the rise.

The study findings appeared in the February issue of Nature Medicine and showed that tests using new semi-synthetic drugs on mice worked as well as, or better than existing drugs against strains of resistant tuberculosis.

The lead author, chemical biologist Richard Lee at St. Jude’s Medical Hospital in Memphis, Tenn., said the study revealed “robust activity” against the bacteria with few side effects, though he said clinical tests in humans could take years.

It’s already taken some time. Five labs across the world worked over four years to redesign the chemical structure of spectinomycin, an existing antibiotic that doesn’t work against tuberculosis. Using crystallography techniques, scientists constructed a 3-D model of the compound so they could see where it binds with TB cells on the atomic level and test newer drug variations.

“TB is unusual in that it has a lot of fatty acids on surface, like a wax jacket to keep the rain out.” Lee said. The study found new mutant synthetic compounds that were able to bind to the greasy bacteria’s ribosome, the place where a cell stores mRNA and synthesizes proteins.

Not only were new compounds able to bind to the ribosome, but three in particular also evaded the TB’s defense mechanism, called efflux.

“Efflux pumps identify and remove foreign agents from a cell,” said Christopher Cooper. “which is great if you’re a cell, but bad if you’re trying to put a compound into the cell and make it do something,”

Cooper is director of chemistry at the TB Alliance, an international non-profit that organizes and funds a large proportion of tuberculosis research, including the St. Jude’s study.

Cooper believes the study’s innovative techniques and discoveries about efflux inhibitors will combine with other drugs in development and help medical research keep up with a terrible, constantly evolving disease.

Tuberculosis kills 1.3 million people annually, sickens 8.6 million worldwide and is second only to HIV/AIDS as the most fatal global disease, according to the World Health Organization.

About 20 percent of global cases are multidrug-resistant, but in some areas like India and China, that number is much higher—and spreading.

“TB in general, is one of humankind’s most prolific killers, and most of that occurs in the developing world, but it’s also moving into areas not in the developing world,” said Derek Ambrosino, a spokesman for the TB Alliance, “What people don’t realize is how arduous and expensive it is to develop a cure.”

Meanwhile tuberculosis cases multiply.

Tuberculosis is transmitted as quick as a touch, but treatment takes much longer—up to two years for multi drug-resistant types. Anne Lenarts says this makes the need to develop more types MDR-TB more urgent.

Lee said the next stage of the study is working on how to administer the drug, what dose and how often: “It’s not just about the ideal treatment,” he said, “it’s also about what patients can bear.”