Macrocyclic antibiotic is more potent than last-resort vancomycin
The first total synthesis of ramoplanin, an antibiotic two to 10 times more active against some gram-positive bacteria than vancomycin, the antibiotic of last resort, has just been achieved by chemistry professor Dale L. Boger and coworkers at Scripps Research Institute [J. Am. Chem. Soc., 124, 5288 (2002)].
Ramoplanin is in Phase II clinical trials for nasal staph infections and Phase III trials for oral treatment of enterococcal infections. The synthesis will provide access to analogs as candidates for stronger or more stable antibiotics.
Ramoplanin is a macrocyclic depsipeptide (a peptidelike compound with both ester and amide linkages) with disaccharide and lipid appendages. There are three types, each having a different lipid. The drug disrupts bacterial cell wall construction by inhibiting glycosyltransferase- and transglycosylase-catalyzed peptidoglycan biosynthesis.
Boger and coworkers have now synthesized the aglycon of ramoplanin A2, the most abundant of the three, and the aglycon of the related compound ramoplanose. The core structure of both is a 49-membered ring containing 17 amino acids.
In the convergent synthesis, three subunits were constructed, coupled, and cyclized to form the ramoplanin core. The lipid group was then added. The coupling of two of the subunits was the most challenging step by far, requiring evaluation of different coupling reagents over several years. The synthesis "provides future access to analogs of the aglycons, which are reported to be equally potent or more potent than the natural products," the researchers note.
Associate chemistry professor Suzanne Walker of Princeton University says the synthesis will aid studies "on how ramoplanin works and what parts of the molecule are important in activity. That may lead to better antibiotics and/or a better understanding of how peptidoglycan synthesis in bacteria is regulated."
Ramoplanin's mechanism of action has been studied by Walker and by assistant professor of biochemistry and biophysics Dewey G. McCafferty of the University of Pennsylvania. McCafferty's team is close to completing a second total synthesis--a solid-phase procedure that "can be easily modified rationally or combinatorially," he says.