A structural model of the penicillin binding protein 2 (PBP2) engaged with the anti-biotic moenomycin. The strands and helical ribbons represent the "backbone" of the PBP2 chain, while the surrounding shapes represent the entire protein structure.

A: The TP domain crosslinks sugars in the bacterial cell wall, strengthening it. Methicillin and related antibiotics bind to this portion of the enzyme and inactivate it. In some methicillin-resistant bacteria, mutation in the TP domain prevents effective antibiotic binding.

B: A linker region joins the TP domain to the GT domain.

C: The GT domain assembles the sugar chains of the bacterial cell wall. The antibiotic moenomycin (yellow, red, and blue) binds to the GT domain, part of which sits within the bacterial cell membrane, which may be the key to preventing antibiotic resistance.

Superbugs, the disease-causing bacteria that are resistant to even the most high-powered antibiotics, are becoming more commonplace.
One dangerous strain called methicillin-resistant Staphylococcus aureus (MRSA), once restricted to hospital wards, is turning up in soccer fields and gym lockers. Doctors are having a hard time keeping up.

Although several new antibiotics to MRSA became available a few years ago, "we're already starting to see resistance to those," says Natalie C. J. Strynadka, an HHMI international research scholar at the University of British Columbia. "You always need a couple more bullets in your arsenal to stay ahead of the game."

In fact, what Strynadka and her Vancouver team would prefer to more bullets is a better bullet—an antibiotic not so readily foiled by bacteria. In their effort to develop one, the researchers focused on an antibiotic called moenomycin. "It's been used in huge quantities in cattle feed," Strynadka says, "and yet we've seen very little resistance."

In fact, says Andrew Lovering, a post-doc in Strynadka's lab, the drug appears to be "resistant" to resistance.

The problem, however, is that moenomycin doesn't work in people. "It's a really complex molecule and is not absorbed well in our bodies," Lovering explains. "We wanted to see if we could change it to make it still effective but amenable to uptake in humans." As a first step, he and his labmates set out to capture a precise atomic picture of moenomycin in midattack on its bacterial target, a membrane-anchored enzyme called penicillin binding protein 2 (PBP2).

As its name suggests, PBP2 is also the protein targeted by penicillin, methicillin, and a host of other conventional antibiotics. The dumbbell-shaped enzyme, tethered by one of its lobes to the bacterial cell membrane, is a molecular knitting machine. It stitches together the cell wall—a dense meshwork of polysaccharide and peptide threads that forms the bacterium's protective outer shell.

Both ends of the enzyme contribute to get the job done. The part anchored to the membrane, called the GT domain, first stitches the sugars into chains that form the main fabric of the cell wall. The other end, called the TP domain, then crosslinks the sugar strands with short peptide chains. Penicillin-type drugs attack the TP domain. Moenomycin is the only well-characterized antibiotic that directly cripples the more mysterious GT domain. In either case, the sabotaged cell wall becomes so weak that the bacterium dies.

Science Illustration: Strynadka lab

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