Antibiotic Halts Lipid Synthesis

A new antibiotic that targets an enzyme in the fatty acid synthesis pathway in bacteria could become a weapon against antibiotic resistance, according to a report from a team of researchers at Merck (Nature 2006, 441, 358). The scientists declined to reveal Merck's current plans for the compound, but they say it remains the subject of intense investigation.

"This target is not totally new, but this compound is exceptionally promising," says Robert E. W. Hancock, a microbiologist at the University of British Columbia, Vancouver. "We desperately need novel drugs to counteract the alarming increase in resistance."

The Merck team, which was led by biologist Jun Wang, structural biologist Stephen M. Soisson, and natural products chemist Sheo B. Singh, found the new molecule, called platensimycin, by fishing it out of a library of 250,000 natural product extracts. The molecule is produced by Streptomyces platensis, a bacterium isolated from a South African soil sample.

Platensimycin inhibits an enzyme in fatty acid synthesis called FabF, one of two enzymes that catalyze the addition of two-carbon units to the growing fatty acid chain. "FabF is one of the critical enzymes in the pathway," Soisson says. "It's essential and it's present in all bacteria that we know of." Other natural products are known to affect this enzyme, but none is used therapeutically.

Finding new targets is particularly important for addressing antibiotic resistance, Wang says. "Working on existing targets, you can improve efficacy, but most likely you cannot overcome target resistance. A novel target will help with this," he says.

The researchers custom-designed a screening assay to search for a FabF inhibitor in the extracts. They engineered a strain of Staphylococcus aureus to produce antisense RNA that gives them tight control of the amount of FabF produced. "By doing that, you make the cell more sensitive to the presence of an antimicrobial that targets that specific gene product," Soisson says. "You increase your sensitivity for detecting things in natural product extracts that may be present in extremely low concentrations." In addition, because the screen is target-based, "you get a preliminary hint at mechanism," he says.

Structural studies were challenging because platensimycin inhibits a short-lived acylated enzyme intermediate in which a structural change allows the antibiotic to block the active site. The transience of the target's conformation was "a big surprise," Soisson says. The researchers obtained crystal structures by making mutant proteins that mimic the acylated enzyme intermediate.

In mice, platensimycin eliminates S. aureus infection. In addition, the antibiotic is effective in cell-based assays against a number of gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant enterococci. Because the drug is rapidly cleared from the body, it requires continuous intravenous delivery.

Christopher T. Walsh, a biochemist at Harvard Medical School who studies antibiotic mechanisms, says, "It remains to be seen if simplified versions of this natural product will be optimized leads, but this natural product should make the fatty acid synthesis pathway a higher priority" as an antibiotic target.