n e w s of t h e
week
Against Bifunctional Antibiotics, Resistance Is Futile
in which they developed an aminoglycoside capable of regenerating itself after it is phosphorylated by a resistance enzyme \J. Am. Chem. Soc, 121, 11922 (1999); C&EN, March 6, page 42]. Mobashery praises the bifunctional approach and notes that there is a precedent for it in the antibiotic imipenem (Merck's Primaxin), which kills bacteria by inhibiting bacterial transpeptidases and also inhibits (3-lactamase resistance enzymes. Julian E. Davies, vice president of research at TerraGen Discovery, Vancouver, British Columbia, who is a pioneer in studies of aminoglycoside resistance mechanisms, says the neamine dimers clearly represent "a novel approach to the modification of aminoglycosides, which would extend their life as effective anti-infective agents. There has not been much success in this area, so the work is worthy of comment. The real question is whether or not these compounds would be less toxic than the natural aminoglycosides." Program director John M. Schwab of the National Institute of General Medical Sciences, Bethesda, Md., which supported the study, says the potency of the most active neamine dimer is high enough "that it's practical to start thinking about structure optimization, with the goal of moving toward clinical evaluation." However, he notes that "the dimers apparently haven't yet been tested in an animal model, so well have to wait and see how toxic and bioavailable they are." Marissa A Miller, antimicrobial resistance program director at the National Institute of Allergy & Infectious Diseases, Bethesda, adds, "We need new products desperately. Over the past
A research team has created a novel type of antibacterial agent designed to combat the growing problem of antibiotic resistance. The antibiotics are bifunctional aminoglycosides that disable or kill bacteria and at the same time inhibit enzymes used by the bacteria to fight back. Aminoglycoside antibiotics are used to treat serious infections. They zap bacteria by binding their ribosomal RNA, thus inhibiting protein synthesis. But their utility has been limited by their high toxicity and the ability of many bacteria to develop resistance. Bacterial enzyme-catalyzed acetylation, phosphorylation, and ribosylation of antibiotics is a pri- Wong mary cause of resistance. Researchers have now synthesized aminoglycoside neamine dimers that not only target ribosomal RNA, but also impede the acetyltransferase and phosphotransferase enzymes that bacteria use to resist aminoglycosides. The work was carried out by postdoc Steven J. Sucheck, assistant professor Pamela Sears, chemistry professor Chi-Huey Wong, and coworkers at Scripps Research Institute, and associate professor of biochemistry Gerard D. Wright and coworkers at McMaster University, Hamilton, Ontario \J. Am. Chem. Soc, 122, 5230 (2000)]. "Each of the two neamine units bind RNA at a different site," Wong says, "and linking them together enhances the RNA binding interaction about 1,000-fold. The dimers also disable or inhibit the enzymes that cause resistance. That's why we call them bi- ™• functional." He points out that Most active dimer has these are the first antibiotics that indiaminobutane linker hibit both bacterial ribosomal RNA and bacterial resistance enzymes. Linker. (CH 2 ) 4 The most potent neamine dimer de1ST veloped by the group is active OH I I against six different types of bacteNeamine Neamine CH 3 CH 3 ria, including an aminoglycosideH9N resistant clinical isolate. Neamine = HO The work is reminiscent of an earHO H9N lier study by chemistry professor H 2 N O^^NH2 Shahriar Mobashery and coworkers \ 0 OH at Wayne State University, Detroit, 12
MAY 29,2000 C&EN
30 years, there's only been one totally new chemical entity licensed as an antiinfective"—the oxazolidinone compound linezolid (Pharmacia's Zyvox). "I would certainly like to see this pursued," Miller says, referring to work on the neamine dimers. "I think that we need to try every new approach that comes down the line in hopes of finding some that will extend the life of existing antibiotics or buy us some time." Stu Borman
3M Study Raised EPA's Concerns There may be more to 3M's recent announcement that it is taking perfluorooctanyl sulfonate (PFOS) products off the market by the end of the year than simply its own concerns over the persistence of these chemicals in the environment and in human and animal tissues. 3M said two weeks ago that it was discontinuing certain Scotchgard brands as well as some surfactants and other products, and in the process emphasized its environmental stewardship in halting production of such persistent materials (C&EN, May 22, page 9). But later, 3M acknowledged it conducted animal tests with the chemicals that raised flags at the Environmental Protection Agency. In 1998, a 3M-conducted rat study linked PFOS-based chemicals to the deaths of rat pups days after they were born. 3M reported these findings to EPA as required under the Toxic Substances Control Act. In the experiments, two generations of rats were exposed to PFOS. More than one-third of the offspring of female rats dosed with 1.6 mg per kg per day of PFOS throughout their pregnancy died within four days of birth. No mortality was observed at lower levels of exposure, 3M says, noting that the PFOS levels that caused the deaths were relatively high. The mechanism behind these findings is unclear, but 3M theorizes that PFOS may inhibit cholesterol biosynthesis in prenatal rats during a critical window when much of the cholesterol that rat pups need is produced. "Rats go through a burst of cholesterol production activity prior to birth," says Larry Zobel, 3M's medical director. "It doesn't appear relevant in humans." Zobel says studies of 3M workers have turned up no illnesses that can be attributed to PFOS exposure, even
