September 22, 2008

Volume 86, Number 38

p. 15

Biochemistry

Antibiotic Ideas

Studies advocate blocking cell-division protein, essential metabolic pathway

Carmen Drahl

WILY BACTERIAL STRAINS are increasingly outwitting antibiotics, but only two new classes of the drugs have been introduced in the last 40 years. Now, two new studies point to additional targets for antibiotic weaponry.

In one study, an international team of researchers coordinated by David J. Haydon of Prolysis, a company specializing in antibacterials, has shown that blocking the protein FtsZ, a bacterial relative of the cell-division protein β-tubulin, is a viable antibiotic strategy (Science 2008, 321, 1673). Meanwhile, a team led by Tohru Dairi of the Biotechnology Research Center at Toyama Prefectural University, in Japan, has uncovered another potential target—an alternative biosynthetic pathway for menaquinones, which are essential electron-transfer compounds for many pathogens (Science 2008, 321, 1670).

Many groups are studying FtsZ as a potential drug target, but the Haydon team's work is "a major advance," says Shahriar Mobashery, a University of Notre Dame chemist who specializes in antibiotics. Until this work, researchers hadn't convincingly shown that blocking FtsZ could kill bacteria, explains Lloyd G. Czaplewski, Haydon's Prolysis colleague and coauthor. Using the technique of fragment-based drug design, the team developed an initial screening hit into antibiotic PC190723. The compound saved mice from lethal doses of Staphylococcus aureus and killed multidrug-resistant S. aureus in culture. Molecular models suggest that PC190723 binds in a pocket adjacent to FtsZ's active site, and additional binding studies indicate that it doesn't interact with human tubulin, Czaplewski says. The scientists declined to disclose their plans for the compound.

Dairi's team screened genome databases and found that some bacteria use a previously unknown series of enzymes to produce menaquinones, electron-transfer compounds that vary in the length of their aliphatic side chains. They further showed that the new pathway is critical for pathogens that cause illnesses such as syphilis but not for humans or beneficial bacteria in the human gut. This makes the pathway an attractive option for making targeted antibacterials, Dairi says.

Bacterial genome sequencing efforts have been very important for the research community, but they alone don't tell the whole story, Mobashery says. Dairi's work is "a tour de force," he adds, because of how the team painstakingly decoded genomic data to discover a functioning metabolic pathway. "We hope to find other unique metabolic pathways in bacteria with the same methods," Dairi notes.

These reports follow a recent study that offers additional support for another antibacterial strategy: keeping bacteria from becoming infectious rather than killing them (Science 2008, 321, 1078).

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