NEWS OF THE WEEK MEDICINAL
CHEMISTRY
in lone-pair electronic repulsion. They used "real mechanistic insight to probe an important therapeutic question in studies achievable only by remarkable practical mastery of the precepts of total synthesis of complex molecules," Walsh comments. Boger's group "may be the only one on the planet that could achieve this synthesis," he says. The study "establishes the inside the vancomycin molecule principle for the first time that HE NATURAL PRODUCT VANcomycin is an antibiotic of has been converted to a methy- tinkering with the natural-prodlast resort, used when other lene. This replacement enhances uct scaffold can give a molecule Crowley antibacterial agents aren't effec- the compound's binding affinity equally active against wild-type tive. But some bacteria have de- for the modified peptidoglycan and resistant forms of this opporveloped resistance to vancomycin. in vancomycin-resistant bacteria tunistic bacterial pathogen." Researchers have now designed yet preserves a substantial amount In another sense, "it is a startand synthesized a revamped form of the antibiotic's affinity for the ing pointforfurther work," Walsh of vancomycin that makes such normal peptidoglycan in vancomy- notes. "An additional 10-fold gain resistance futile, or at least a lot cin-sensitive bacteria. The analog in affinity would generate a useis thus 100-fold more active than fully potent antibiotic to replace more difficult. Bacteria such as Staphylococcusvancomycin against vancomycin- vancomycin." At present, "the total aureus, a cause of food poisoning resistant bacteria but only 3% as synthesis is not ready for process and a source ofhospital infections, active as the drug against vanco- development nor for biosynthetic development," he says. have developed resistance to a mycin-sensitive bacteria. number of antibiotics but not to Boger says that his group is cur"This is an important breakvancomycin—yet. When they do through and will help medicinal rently trying to improve analog develop resistance to vancomycin, chemists rationally design new activity and that the synthetic Boger "as many suspect is just a matter of antibacterial agents," says assistant problem is solvable. One could time, we will be in trouble," says professor of chemistry and chemistry professor Dale L. Boger biochemistry Yong Gao of of Scripps Research Institute. Southern Illinois University, In an effort to prepare for such Carbondale, whose research an eventuality, graduate student interests include peptidoglyBrendan M. Crowley and Bo- can-targeted antibacterial ger reengineered vancomycin to agents. "The model vancomake it much more resistance- mycin analog in this paper proof and devised a way to syn- is only available through thesize the modified version from chemical synthesis, which simple starting materials (Jf. Am. suggests that organic chemChem. Soc, published online Feb. 4, ists can play unique and important roles in studydx.doi.org/10.1021/ja0572912). Vancontyrin works as an antibi- ing complicated biological otic by binding to a peptidoglycan systems." that is essential to the biosynthesis In earlier work, Christopher possibly prepare the analog from DEEP IMPACT of bacterial cell walls. The most T. Walsh, professor of biological vancomycin itself—"We just have Crowley and Boger common form of resistance is due chemistry and molecular phar- not yet discovered a way to do it," modified vancomycin to a modification that changes a macology at Harvard Medical he says. "Access to the drug by by changing a key peptidoglycan amino acid from School, and coworkers had de- synthesis is not out of the ques- carbonylgroup D-alanine to D-lactate. This muta- termined the molecular basis of tion. A good process group might buried deep in tion greatly reduces the affinity of vancomycin resistance to be a be able to work wonders with the the molecule vancomycinforthe peptidoglycan, three order of magnitude drop in basic route we developed. And a to a methylene rendering it ineffective. the drug's affinity for the modi- genetically engineered organism (red), making the Crowley and Boger compen- fied peptidoglycan. Boger and might be coaxed to produce ana- agent much more sated with a comparably simple coworkers studied the detailed logs or analog precursors." Such resistant to bacterial change to vancomycin. They interactions that caused this loss efforts might lead to an even bet- resistance. synthesized an analog in which a of affinity, tracing it to a missing ter antibiotic of last resort.—STU carbonyl group positioned deep hydrogen bond and an increase BORMAN
VANCOMYCIN REDESIGNED
Antibiotic of last resort is modified to combat bacterial resistance
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