Switch hitters: antibacterial compounds target new mechanism to kill microbes.

With drug-resistant bacteria on the offensive, researchers are on the lookout for novel microbial processes to disrupt. A new study provides evidence that recently discovered ribonucleic acid segments may become plum targets.

Those riboswitches, found in many bacteria, are stretches of messenger RNAS, which provide the instructions to cells for making specific proteins (5N: 4/10/04, p. 232). Typically, riboswitches respond to cellular concentrations of certain compounds that a cell requires. The switches then control the expression of genes necessary for making those metabolites.

Since the discovery of riboswitches in 2002, researchers have reported a dozen classes, each of which responds to a different metabolite. For example, many bacteria have riboswitches that interact with the amino acid lysine. When a cell has sufficient lysine, the amino acid binds to the riboswitch, triggering a structural change that blocks manufacture of the first enzyme in lysine production.

Although there are examples of riboswitches in plants and fungi, riboswitches have yet to be found in people, notes Ronald R. Breaker, the chemical biologist at Yale University whose team gave riboswitches their name.

Breaker suspected that those RNA segments might make good targets for drug development. Breaker's group had shown that two previously identified antibacterial agents work in part by binding to riboswitches.

In the new work, the team created a series of compounds designed to shut down lysine synthesis in Bacillus subtilis, thereby inhibiting growth. The researchers' strategy was to modify lysine so that it would still bind to the riboswitch but the rest of the cell's biomachinery wouldn't recognize it.

"We don't want to give [the microbe] food or a precursor it can easily convert" to lysine, Breaker says.

The researchers found three compounds that inhibit microbial growth by acting on the lysine riboswitch, they report in the January Nature Chemical Biology.

Breaker notes that the lysine riboswitch probably isn't the best one to target to fight bacteria. In their study, the researchers could stop bacterial growth only when the culture medium contained no lysine. The group is now focusing on a different class of riboswitches.

Nevertheless, the work just reported "establishes the biochemical basis" for targeting riboswitches with drugs, says chemical biologist Joseph A. Piccirilli of the University of Chicago. "You might be able to use that logic to choose or design a [drug] for a different riboswitch."

"Nobody has thus far carried out a concerted screen [of chemicals[ against these targets," says structural biochemist Adrian R. Ferre-D'Amare of the Fred Hutchinson Cancer Research Center in Seattle. With the evidence so far, he says, that approach is worth trying.