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Spiral structure key to TB’s drug resistance

IOWA STATE (US) — Using X-ray crystallography, scientists have zoomed in on the tuberculosis bacterium to find out how it resists multiple drugs.

Edward Yu took note of the facts—nearly 2 million deaths each year, 9 million infected each year, developments of multidrug-resistant, extensively drug-resistant and now totally drug-resistant strains—and decided to shift his research focus to tuberculosis.

Yu has described in the journal Nature the three-part structure that allows E. coli bacteria to pump out toxins and resist antibiotics.

And now, in a paper published online by the journal Nucleic Acids Research, a research team led by Yu describes the structure of a regulator that controls the expression of the multidrug efflux pump in Mycobacterium tuberculosis.

This latest study is a starting point for a better understanding of how the tuberculosis bacterium is able to resist drugs, says Yu, professor of physics and astronomy, of chemistry, of biochemistry, biophysics, and molecular biology in Iowa State’s College of Liberal Arts and Sciences and an associate of the US Department of Energy’s Ames Laboratory.

The development of strains totally resistant to drugs “inspired us to move in this direction and try to understand the mechanism in developing drug resistance,” Yu says.

“It is obvious that the emergence of these drug-resistant TB strains has evolved into a major threat and challenges our global prospects for TB control,” Yu’s research team writes in its latest paper.

“Thus, knowledge of the molecular mechanisms underlying drug resistance in M. tuberculosis is essential for the development of new strategies to combat this disease.”

Prior to Yu’s study, not much was known about the structure and function of the tuberculosis efflux pump regulator known as Rv3066.

That, in part, is because researchers have attributed drug resistance in tuberculosis to the bacterium’s very thick cell wall. That wall makes it very difficult to get drugs into the bacterium.

The researchers used X-ray crystallography (including X-ray beams produced by the Advanced Photon Source) to study the Rv3066 structure. They collected data showing the regulator when the toxic compound ethidium bromide was present and when it was not.

The data reveal an asymmetric, two-part molecule with a spiral structure. The structure is flexible, allowing the regulator to recognize and respond to multiple drugs. In the presence of ethidium, Yu’s group says the regulator responds with a rotational motion, inducing expression of the efflux pump that rids the bacterium of antimicrobial drugs.

Studying that structure and mechanism could make a difference in the fight against drug-resistant tuberculosis: “Elucidating the regulatory systems of multidrug efflux pumps in M. tuberculosis,” Yu and the researchers write in their paper, “should allow us to understand how this bacterium contributes to multidrug resistance and how it adapts to environmental changes.”

In addition to Yu, the research team includes additional investigators from Iowa State, the Ames Laboratory, and Cornell University.

Yu’s research is currently supported by the National Institutes of Health. The researchers’ use of the Advanced Photon Source at Argonne National Laboratory in Argonne, Illinois, was supported by the US Department of Energy’s Office of Basic Energy Sciences.

Source: Iowa State University

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