ANTIBIOTIC IDEAS BIOCHEMISTRY: Studies advocate
blocking cell-division protein, essential metabolic pathway
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ILY 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 multidrugresistant S. aureus in culture. Molecular models suggest that PC190723 binds in a pocket adjacent to FtsZ’s ac-
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tive 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 Molecular model shows how Prolysis’ side chains. They further showed that the new pathway antibiotic binds is critical for pathogens that cause illnesses such as to a bacterial cellsyphilis but not for humans or beneficial bacteria in the division protein. human gut. This makes the pathway an attractive option for making targeted antibacterials, Dairi says. Bacterial genome sequencing efforts have been very important for NH2 O the research community, but they alone don’t tell the whole story, F F Mobashery says. Dairi’s work is “a tour de force,” he adds, because of S O how the team painstakingly decoded N N genomic data to discover a functioning metabolic pathway. “We hope to PC190723 find other unique metabolic pathCl ways in bacteria with the same methO ods,” Dairi notes. These reports follow a recent study that offers additional support for an( ) 7 other antibacterial strategy: keeping O bacteria from becoming infectious rather than killing them (Science Menaquinone 8 2008, 321, 1078).—CARMEN DRAHL
INDUSTRIAL BIOTECHNOLOGY Goodyear and Genencor plan biobased isoprene In the U.S. most isoprene is a by-prodGoodyear Tire & Rubber and the enzymes uct of the ethylene industry, according to company Genencor are collaborating the market research firm SRI Consulting. on the R&D of a fermentation route to Goodyear is one of the world’s isoprene, an important synthetic largest consumers of isoprene, rubber raw material. using it to produce polyisoprene, The partners say that BioIsoconsidered the synthetic version prene, as they call the biotech Isoprene of natural rubber. Genencor figures isoprene, could make the tire and that the world market for isoprene rubber industry less dependent is worth as much as $2 billion per year. on petroleum-derived products. “Since Although they are only now disclosing synthetic rubber is a critical component the project, the companies say they have to our products, we are very excited to been working together for more than a be working on this renewable alternative year. Over the next three years, Genencor with Genencor,” says Jean-Claude Kihn, says, it will invest about $50 million to Goodyear’s chief technology officer.
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further develop its microbial fermentation technology and scale up production. The company, a subsidiary of Denmark’s Danisco, expects to be technically ready by 2010 and to commission a large-scale plant by 2012. Biobased chemicals are a popular research topic these days, but few have been successfully commercialized. Genencor can claim participation in one such product: DuPont’s Sonora propanediol, which is made in Loudon, Tenn., out of corn sugar. Genencor is also working with DuPont on cellulose-based ethanol. —MICHAEL MCCOY
