Killing Resistant Germs

Although a number of new antibiotics have been discovered in recent decades, our armory against infection is continually being depleted, as our microscopically small enemies are crafty warriors that develop resistance to current antibiotics.

Multiresistant bacteria are a big problem, especially in hospitals. Already weakened patients are easy victims, for which an infection that cannot be treated with antibiotics can quickly become life-threatening. What is needed are active agents that act on completely different sites in the physiological sequence of pathogens than current medicaments. Platensimycin, recently isolated from the mushroom Streptomyces platensis, is such an agent. A Californian team of researchers is now the first to synthesize this natural product completely in the laboratory—a crucial step on the way to a new class of antibiotics.

Platensimycin inhibits an important step of bacterial fatty acid biosynthesis and in this way paralyzes a broad spectrum of Gram-positive bacterial strains. Thus, this natural product in able to kill dangerous germs that have developed resistance not only to established antibiotics but also to standby products. Examples of these include various resistant strains of Staphylococcus aureus and Enterococcus faecium.

To isolate a complex natural product in sufficient quantity and purity for further experiments is usually a difficult and time-consuming, if not impossible, task. Chemists thus follow a different path: They reproduce the natural product in the laboratory from the ground up. This approach is known as total synthesis. To devise such a total synthesis is an enormous scientific challenge. A way must be found to assemble a complicated synthetic molecule faultlessly from simple, available components—and in sufficiently high yield in each reaction step. The total synthesis of platensimycin has now been accomplished by a team headed by the renowned natural products chemist K. C. Nicolaou (The Scripps Research Institute, La Jolla, and University of California, San Diego). Platensimycin consists of an unusual aromatic ring coupled through an amide group to a compact cage structure. The team built these two components—each a veritable challenge for synthetic chemists—separately and then joined them in the final step of the synthesis. “The described chemistry,” says Nicolaou, “sets the stage for the synthesis of designed analogues for structure–activity relationship studies in the search for new antibacterial agents.”