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How bacteria resist antibiotics

IOWA STATE (US) — Researchers have discovered the crystal structures of pumps that remove heavy metal toxins from bacteria, making them resistant to antibiotics.

The finding offers a better understanding of bacterial resistance to antibiotics that could ultimately help drug researchers develop treatments to combat that resistance.

The findings are published in the Sept. 23 issue of the journal Nature.

Researchers purified and crystallized the membrane proteins that make up an efflux pump of E. coli bacteria. Some samples contained the toxic heavy metals copper and silver and some did not.

They used X-ray crystallography to compare the various structures, identify the differences, and understand the mechanism that removes heavy-metal toxins from cells.

The paper specifically describes the crystal structure of CusA, one of three parts of the pumps responsible for removing toxins from bacteria.

CusA is an inner membrane transporter which belongs to the resistance-nodulation-division protein superfamily, says Edward Yu, associate professor of chemistry, physics and astronomy, biochemistry, biophysics, and molecular biology at Iowa State University.

It consists of 1,047 amino acid residues and spans the inner membrane 12 times.

What those pumps do, is “recognize and actively export these substances out of bacterial cells, thereby allowing the bugs to survive in extremely toxic conditions,” Yu says.

“This work reports the first detailed structure of a unique heavy metal transporter that enables bacteria to survive the toxic effects of silver and copper,” explains Jean Chin, who oversees this and other structural biology grants at the National Institutes of Health.

“By detailing the exact steps that a metal ion is likely to take through the transporter, this study suggests how we might block the pathway and render pathogenic bacteria sensitive to heavy metal toxins.”

Yu, who has been studying bacterial resistance to antibiotics for nearly a decade, says direct information about how bacteria handle heavy-metal toxins is important information for biomedical researchers.

“We want to understand the mechanisms of these heavy-metal pumps,” he explains. “And that could allow biotechnology researchers to make inhibitors to stop the pump and the antibiotic resistance.”

Researchers from Argonne National Laboratory, managed by Cornell University, contributed to the study, which was supported by the National Institutes of Health.

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