In mapping the structure of short-lived bacterial 'switches,' biochemist may find novel answer to antibiotic resistance

December 22, 1999

WALTHAM, Mass. -- Atom by atom, a Brandeis University researcher and her colleagues have unmasked the structure of ephemeral protein "switches" that play a critical role in transforming mild-mannered bacteria into lethal parasites. The finding, reported in the Dec. 23 issue of the journal Nature, raises the prospect of a novel kind of antibiotic to fill the void left by growing resistance among many bacteria to traditional drugs.

The research, led by Brandeis biochemist Dorothee Kern, also involved scientists from the University of Wisconsin, Lawrence Berkeley National Laboratory, and the University of California at Berkeley.

Current-generation antibiotics, which kill off normal strains of bacteria while leaving resistant ones unaffected, essentially select for the survival of resistant strains, sometimes inducing resistance in as little as six months. The protein family Kern describes in the Nature paper represents a potential target for a whole new class of antibiotics to specifically prevent pathogenic bacteria from becoming virulent and attacking the body's cells.

"Most conventional antibiotics work by inhibiting processes essential to cell viability, such as DNA translation or the assembly of cell membranes," says Kern, an assistant professor of biochemistry at Brandeis. "Few attempts have been made to target the mechanisms by which pathogenic bacteria become virulent and infect host cells."

Part of a two-component system that dominates signal transduction in bacteria, the phosphate-juggling protein switch mapped out by Kern and her colleagues works by snatching a single phosphate ion from the amino acid histidine. The phosphorylated protein then binds to bacterial DNA, turning on genes such as those that instigate infection. These protein switches are ubiquitous in bacteria, but aren't found in humans -- making them an ideal target for antibiotics.

The protein switch studied by Kern is part of a common two-component system wherein a biological signal prompts a histidine molecule on one component to transfer a phosphate ion to an aspartate molecule on a second component. A strikingly similar two-component mechanism operates among many species of bacteria. "Our goal was to unravel the structural basis of the switch in the signal cascade at atomic resolution, with the hopes of developing new approaches for treating multiple-resistant infections," Kern says.

It's the first time the structure of such a short-lived protein has ever been pinpointed by scientists, Kern says, and heralds new possibilities for future NMR imaging of other evanescent biomolecules.

Key to the research was an innovative approach to nuclear magnetic resonance (NMR) spectroscopy that allowed Kern to regenerate, for a day and a half, the fleeting active configuration the protein switch normally assumes only during the few minutes when it grabs and holds a phosphate ion. The rapid loss of these ions -- necessary for fast responses to the environment -- usually makes the active, phosphate-bound form of the switch far too transient for structural analysis. To keep the protein switch in its active state long enough to get a good snapshot, Kern collected NMR spectra on the protein during catalysis using a constant stream of phosphate.

Kern's co-authors on the paper are Brian F. Volkman of the University of Wisconsin, Sydney Kustu of the University of California at Berkeley, and Peter Luginbühl, Michael J. Nohaile, and David E. Wemmer of the Lawrence Berkeley National Laboratory. The research was sponsored by the U.S. Department of Energy and the National Science Foundation.

Brandeis University

Related Bacteria Articles from Brightsurf:

Siblings can also differ from one another in bacteria
A research team from the University of Tübingen and the German Center for Infection Research (DZIF) is investigating how pathogens influence the immune response of their host with genetic variation.

How bacteria fertilize soya
Soya and clover have their very own fertiliser factories in their roots, where bacteria manufacture ammonium, which is crucial for plant growth.

Bacteria might help other bacteria to tolerate antibiotics better
A new paper by the Dynamical Systems Biology lab at UPF shows that the response by bacteria to antibiotics may depend on other species of bacteria they live with, in such a way that some bacteria may make others more tolerant to antibiotics.

Two-faced bacteria
The gut microbiome, which is a collection of numerous beneficial bacteria species, is key to our overall well-being and good health.

Microcensus in bacteria
Bacillus subtilis can determine proportions of different groups within a mixed population.

Right beneath the skin we all have the same bacteria
In the dermis skin layer, the same bacteria are found across age and gender.

Bacteria must be 'stressed out' to divide
Bacterial cell division is controlled by both enzymatic activity and mechanical forces, which work together to control its timing and location, a new study from EPFL finds.

How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.

The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?

Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.

Read More: Bacteria News and Bacteria Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to