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Bacteria use pump to resist drugs

IOWA STATE (US) — Researchers have uncovered two parts of the three-part crystal structures of pumps that recognize and remove heavy metal toxins from bacteria.

It is believed that understanding how the three parts work together will help scientists find ways to restore the effectiveness of antibiotics.

The research is reported in the journal Nature.

“These pumps have to assemble together in order to pump out heavy metals and antibiotics,” says Edward Yu, associate professor of physics and astronomy, chemistry,  biochemistry, biophysics, and molecular biology at Iowa State University.

“Researchers may be able to use these findings to design an inhibitor so the pump can’t be assembled and can’t work.”

The current paper describes the inner membrane transporter and how it interacts with the pump’s middle adapter, known as CusB.

Yu described the first part of the pump—the inner membrane transporter known as CusA—in an earlier issue of Nature. The two parts together are known as the CusBA complex.

Researchers purified and co-crystallized the proteins that make up the transporter and adaptor parts of the efflux pump from E. coli bacteria and then used X-ray crystallography, including a technique called molecular replacement with single-wavelength anomalous dispersion, to determine the structure and interaction of the two parts.

The study revealed molecule by molecule, how the inner transporter’s three molecules bind and interact with the middle adaptor’s six molecules. The studies also revealed the adaptors’ six molecules form a funnel-like channel extending from the top of the transporter.

Using these discoveries, the researchers can predict how the three-molecule structure of the pump’s third part, the outer membrane channel known as CusC, interacts with the CusBA complex.

Discovering the structure of the toxin pump is a significant step toward a better understanding of bacterial resistance to antibiotics, Yu says.

“A crystallographic model of this tripartite efflux complex has been unavailable,” the researchers wrote in a summary of their latest Nature paper, “simply because co-crystallization of different components of the system has proven to be extremely difficult.”

“Determining the structure of CusBA represents a remarkable achievement that has enabled Dr. Yu and his collaborators to model the structure of the entire CusCBA complex,” says Jean Chin, who oversees structural biology grants at the National Institutes of Health.

“This advance has brought novel insights on how the transporter functions and could lead to ways to block its activity and heighten bacteria’s sensitivity to antibiotics.”

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

More news from Iowa State University: www.news.iastate.edu/

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