New 'Twist' In Proteins Offers Possible Route To Improved Antibiotics

April 29, 1996

DURHAM, N.C. -- Biochemists using X-ray crystallography to figure out the structure of an enzyme critical to the growth of many bacteria have discovered an extremely unusual "left-handed" spiral structure in the molecule.

The finding suggests the possibility of a new kind of antibiotic that could recognize the unusual structure, jam the enzyme and kill bacteria. Bacteria would find it extremely difficult, if not impossible, to develop resistance to such a drug, since the enzyme, called LpxA, is necessary to bacterial growth, the scientists said.

Bacterial resistance to antibiotics has become an important health problem and one that has defied solution, since bacteria can so readily adapt to the current generation of antibiotics.

The researchers, who published their findings in the Nov. 10 issue of the journal Science, are Christian Raetz, chairman and professor in the Duke University Medical Center department of biochemistry, and Steven Roderick, assistant professor at the Albert Einstein College of Medicine department of biochemistry. Their research is sponsored by the National Institutes of Health.

In the report, Raetz and Roderick reported X-ray crystallographic studies of LpxA from the common gut bacterium Escherichia coli. The LpxA enzyme catalyzes the first step in synthesis of the lipid that makes up the outer membrane of the bacteria. Specifically, LpxA catalyzes the transfer of the 14-carbon fatty acid hydroxymyristate, to the acceptor, UDP-N-acetyl glucosamine, and functions as the first step of lipid A biosynthesis. Lipid A serves as the outermost coat of bacteria like E. coli. Thus, LpxA is "essential for bacterial growth as well as the maintenance of the permeability barrier function of the outer membrane," the scientists said.

Like all protein enzymes, LpxA consists of a long chain of amino acids that folds itself into the compact structure, which constitutes the functioning enzyme. These folded enzymes may include roughly globular shapes, or spiral helices, the known examples of which are "right-handed." That is, when viewed end on, the helix spirals away in a clockwise direction.

In earlier research, Raetz and his colleagues had discovered that the amino acid sequence of the LpxA enzyme contained sequences similar to several other enzymes with similar function, although the three-dimensional structure of the enzymes had not yet been determined.

The Science paper reported that Roderick's X-ray crystallography of the enzyme revealed that it consists of three identical subunits that fit together to form the functioning enzyme. Each subunit consists of a novel "left-handed" beta helix at the end called the NH2-terminal. The other end of the enzyme, called the COOH-terminal, features coils called alpha helices that are far more common protein structures. The crystallography revealed that the left-handed beta helices were triangular in shape, with each side of the triangle formed from a roughly repeated six-amino acid, or hexapeptide, sequence. According to Raetz, the finding of the unusual structure suggests that other enzymes with similar sequences also form the left-handed helix.

"There is a long list of similar hexapeptide repeats in the scientific literature," Raetz said, "but none has had its X-ray structure done."

According to Raetz, the unusual left-handed helical structure may offer a unique target for a new generation of antibiotics designed to home in on the structure. The left-handed structure also offers a new "twist" to biochemists attempting to design and construct proteins for use as medicines and chemical probes.

The researchers' next step will be to pinpoint the LpxA enzyme's "active site," which is the part of the protein that actually catalyzes the chemical reaction. Any successful antibiotic must plug into the active site, blocking its action, to kill the bacteria.

At Duke, Raetz and his colleagues are planning experiments in which they selectively alter various amino acids in the enzyme and then study the effects of those alterations, to understand how the natural enzyme works. Roderick is currently attempting to locate the active site by determining the X-ray structure of the enzyme with one of its bound substrates.

In a first step toward developing antibiotics that would block the enzyme's activity, the Duke scientists also are planning to survey known chemicals that might fit into the cleft of the active site.

"Conceptually, it would seem feasible to design drugs that could act as antibiotics for all gram-negative bacteria, which produce about half of all infections," Raetz said. "It would be difficult, because bacteria are different from one another, but the discovery of this common structure in an enzyme critical to bacterial growth certainly offers considerable promise."

Duke University

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