New antibiotic dulls bacterial senses.

To perceive the world and react to it, people rely on their eyes, ears, and other sensory organs, which send electrically coded information via nerve cells to the brain. In contrast, bacteria tend to use much simpler, two-protein relays to govern their responses to changes in the external environment.

"These two-component systems, are the eyes and ears of the bacteria," says microbial geneticist Thomas J. Silhavy of Princeton University. "[They] control the expression of all the genes that are important for survival in various environmental circumstances."

Investigators searching for new antibiotics have now found a compound that seems to inhibit the first half of these signaling systems, a family of proteins known as kinases. In test-tube experiments, the compound stalls the growth of many bacteria, even recalcitrant strains that have acquired resistance to other antibacterial drugs. James A. Hoch of the Scripps Research Institute in La Jolla, Calif., and his colleagues report their findings in the April 28 Proceedings of the National Academy of Sciences.

As antibiotic resistance has grown steadily into a pressing issue, scientists have sought drugs that take aim at different bacterial targets than those attacked by traditional antibiotics. The two-component signal pathways, which consist of a kinase and a protein called a transcription factor, make an appealing choice because bacteria use the pathways but animal cells do not.

Researchers have recently found that although some microbes have no two-component signal pathways, others employ several dozen of these kinase-transcription factor relays.

The pathways usually govern bacterial virulence genes, whose activity is vital to establishing an infection or causing disease in a host. For example, when certain bacteria reach a person's lungs, a particular kinase is activated. The kinase then chemically modifies its partner transcription factor, enabling it to bind to DNA and turn on the genes required to initiate a lung infection.

To identify potential new antibiotics, Hoch's team, working with scientists at the R.W. Johnson Pharmaceutical Research Institute in Raritan, N.J., searched for compounds that would prevent the activation of a bacterial kinase, KinA, which is part of a two-component relay The investigators identified a compound that thwarts the growth of many strains of bacteria--including troublesome ones that resist antibiotics such as penicillin and vancomycin--and kills a drug-resistant strain of Staphylococcus aureus.

Hoch and his colleagues also found that bacteria develop resistance more slowly to the KinA inhibitor than to a traditional antibiotic. They speculate that the compound may inhibit several kinases, making it difficult for bacteria to develop mutations that overcome the drug.

Some researchers have expressed skepticism about developing drugs that target the kinases in signaling systems, arguing that such compounds wouldn't kill bacteria directly. However, a few recent studies have shown that some of these two-component pathways are essential for the survival of bacteria.

Moreover, reducing a bacterium's virulence could give a person's immune system time to eliminate the microbe before it causes problems. "If you had an inhibitor of a large number of the kinases, the bacteria would be deaf, dumb, and blind," Silhavy says. While such an inhibitor sounds promising, he cautions that it must prove itself through tests in animals and eventually people.