TB or not TB: Efflux X-rayed
- Published: Sep 1, 2012
- Author: David Bradley
- Channels: X-ray Spectrometry
In a previous issue, we discussed early work on Escherichia coli as a proof of principle for understanding how bacterial resistance to antibiotics can emerge. Now, Edward Yu's team at Iowa State University have taken another step forward in our understanding of this pressing issue by using crystallography to reveal the structure of a protein regulator that controls the expression of the multidrug efflux pump in Mycobacterium tuberculosis.
Yu was particularly concerned by the fact that despite the public perception of TB being an archaic disease with which few people suffer, there are almost 9 million people infected each year and some 2 million deaths annually. Multidrug-resistant strains of the bacteria have emerged in recent years in the developing world and the deprived inner cities of the West. His earlier work revealed the three-part structure that allows E. coli bacteria to pump out toxins and resist antibiotics and now his focus is on drug-resistant TB.
Writing in the journal Nucleic Acids Research, Yu and his colleagues explain how this latest study is just a starting point for improving our understanding of how the tuberculosis bacterium can beat even the most potent of drugs in our antibiotic arsenal. The emergence 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.
He points out that, "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." Identifying the biomolecular mechanisms that underpin drug resistance in M. tuberculosis is critical to devising novel pharmaceutical strategies that might yet be able to combat this lethal disease.
Until now, little was known of the structure or function of the tuberculosis efflux pump regulator known as Rv3066. This dearth of information is partly blamed on the fact that researchers had simply assumed that the thick cell wall of the TB bacterium was the root of its great drug resistance capacity, which makes it physically very difficult to get drugs inside to kill the microbe.
The study used resources at the Advanced Photon Source facility of Argonne National Laboratory in Argonne, Illinois with financial backing from the US Department of Energy's Office of Basic Energy Sciences. The team used X-ray crystallography to get a clearer view of the Rv3066 structure in the presence and in the absence of the toxic compound ethidium bromide.
Their structure showed an asymmetric, two-part molecule with a flexible spiral structure. This flexibility allows the protein to recognize and respond to drugs of many different shapes and sizes. In their experiments, ethidium causes the regulator to respond with a rotational motion, that would under normal circumstances induce the efflux pump to expel the toxin.
"Elucidating the regulatory systems of multidrug efflux pumps in M. tuberculosis should allow us to understand how this bacterium contributes to multidrug resistance and how it adapts to environmental changes," the team explains. Such important clues might lead to a way to somehow inhibit this protein's flexibility and so allow an antibiotic to do its job unhindered and treat the disease.
Yu worked alongside Iowa State's Qijing Zhang, senior research associate Kanagalaghatta Rajashankar from Cornell University in Ithaca, New York and Feng Long, Chih-Chia Su, Lei Dai, Jani Reddy Bolla, Sylvia Do, Hsiang-Ting Lei, Xiao Chen, Jillian Gerkey and Daniel Murphy.
- Nucleic Acids Res, 2012, online: "Structural and functional analysis of the transcriptional regulator Rv3066 of Mycobacterium tuberculosis"
Article by David Bradley
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
- Achema 2012 (381)