Unnatural Success (New Antibiotic?)

Chemists report the first synthesis of a promising antibiotic that other researchers recently discovered in nature. With the recipe in hand, scientists can pursue modifications that might make the compound more effective.

Earlier this year, a team from Merck Research Laboratories announced the discovery of platensimycin, a small molecule produced by the bacterium Streptomyces platensis (SN: 5/20/06, p. 307: http://www.sciencenews.org/articles/20060520/fob1.asp). Platensimycin killed certain drug-resistant pathogens by disrupting their synthesis of fatty acids.

After seeing that "exciting report," K. C. Nicolaou of Scripps Research Institute in La Jolla, Calif., says, he and his colleagues devised a strategy to synthesize the compound. The 16–step lab process builds the compound's two halves separately and then joins them.

The researchers describe their work in the Oct. 27 Angewandte Chemie International Edition.

Nicolaou's group is now working to improve the synthesis strategy and to modify the antibiotic. For instance, the Merck team had found that mice required a continuous infusion of the drug, an indication that the drug might break down too quickly to be effective in people. Nicolaou says that his team will try to develop longer-lasting forms of the compound.

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This is the article referenced above:

Week of May 20, 2006; Vol. 169, No. 20 , p. 307

Bug Zapper: Novel drug kills resistant bacteria

Nathan Seppa

A newly recognized compound can wipe out some of the most troublesome antibiotic-resistant bacteria, laboratory tests show. The drug works by sabotaging a microbe's production of fatty acids.

Scientists at Merck Research Laboratories in Rahway, N.J., discovered the compound, which they call platensimycin.

The findings are preliminary but impressive, says Eric D. Brown, a microbiologist at McMaster University in Hamilton, Ontario. "This is a really promising story in a field that has had quite a bit of disappointment," he says.

Roughly 90,000 people in the United States acquire fatal infections in hospitals every year, according to data from the Centers for Disease Control and Prevention in Atlanta. Nearly three-fourths of those deaths can be traced to antibiotic-resistant microbes.

Most antibiotics were developed at least 50 years ago (SN: 5/28/05, p. 347: Available to subscribers at http://www.sciencenews.org/articles/20050528/bob9.asp). Those made more recently are almost all variants of the early drugs and work by attacking the bacterial cell wall or DNA- or protein-synthesis machinery.

Merck chemist Sheo B. Singh and his colleagues screened roughly 250,000 natural compounds in search of potent antibacterials. This approach makes sense, Brown says, because organisms in nature "are constantly in warfare with each other." He notes that natural compounds work well as drugs because they target specific weaknesses in rival organisms.

The search led to platensimycin, a small molecule made by the bacterium Streptomyces platensis. That bug normally lives in soil in South Africa.

In the May 18 Nature, the researchers report that platensimycin promptly kills lab-dish colonies of staphylococcus and enterococcus bacteria that resist drugs such as vancomycin and methicillin. When the researchers continuously infused mice with the drug in a first test, it killed Staphylococcus aureus that wasn't drug resistant.

Platensimycin is structurally different from other antibiotics. Unlike most of those drugs, it binds to and neutralizes an enzyme called FabF, which bacteria use to make fatty acids. Platensimycin "preexisted in nature to get this job done," Brown says. "This was pretty good detective work at Merck."

Fatty acids are essential for building and maintaining the membrane that lines the bacterial cell wall. FabF is different from the corresponding enzyme in mammals, suggesting that platensimycin won't inhibit fatty acid synthesis in people, says Charles O. Rock, a biochemist at St. Jude Children's Research Hospital in Memphis, Tenn.

This is the fourth natural compound—and by far the most potent—found to target FabF, Rock notes. "Nature is telling us again and again that if you want to go after bacteria, go after this enzyme," he says.

"If we look long enough and hard enough, we'll find these [fatty acid] inhibitors," says Steven J. Projan, a microbiologist at Wyeth Pharmaceuticals in Cambridge, Mass. But he cautions that the Merck team found it necessary to continuously infuse the drug in the mouse tests. That suggests that platensimycin might be metabolized too quickly in people to make a good drug candidate. Still, the study shows that derailing fatty acid synthesis can kill bacteria, Projan says.

The new finding "just goes to show you how marvelously clever nature is at blocking enzyme activity," says Brown.

Despite the heady results, the Merck scientists had no comment on whether the company would pursue further development of platensimycin.

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