Lovering, Strynadka, and their colleagues sought to purify and crystallize moenomycin-bound PBP2 to determine the three-dimensional structure of the complex by x-ray crystallography. By understanding how moenomycin binds and interacts with PBP2, explains Strynadka, "we could ask what is really important in the moenomycin molecule for inhibition, and what can we get rid of to make this a smaller compound, with better pharmacokinetic properties so it will work in humans?"

Proteins like PBP2 are notoriously difficult to extract from their membranes in a way that preserves their native structure. Lovering and research assistant Liza H. de Castro persevered for three years to find just the right conditions to purify and crystallize the protein, on top of an additional two years invested by Daniel Lim, a postdoc previously in the lab. The long-anticipated results, reported in the March 9, 2007, issue of Science, offer drug designers a wellspring of information. "Our structure tells us exactly what the key components are that allow moenomycin to bind to the GT domain," says Strynadka. It also enables them to define the smallest possible part of moenomycin that will react with PBP2, key to reducing the antibiotic's size for use in humans.

The researchers also found that the bacterial membrane, which caused so much frustration, might be a large factor in helping the moenomycin-PBP2 reaction fend off resistance, Strynadka says. "From what our structure shows, the GT enzyme activity appears to work within the membrane. And perhaps that protects the enzyme from modifications that would normally be part of a resistance phenomenon."

Sounds like the makings of a better bullet against the toughest germs.

	PAGE 2 OF 2	Back