Ramoplanin May Be the Antibiotic of the Future

A new antibiotic called ramoplanin targets vancomycin-resistant organisms by interfering with and inhibiting the use of peptidoglycan, a major structural molecule essential for bacterial cell wall support, a finding that may aid the development of new classes of antibiotics. A study describing how ramoplanin functions at the molecular level appeared in the May 21, 2002, online edition of the Proceedings of the National Academy of Sciences. The antibiotic is now in phase III trials.

Ramoplanin inhibits peptidoglycan synthesis after the formation of cytoplasmic precursors, at a step distinct from the site of action of vancomycin. In fact, ramoplanin has been found to be up to ten times as powerful as vancomycin, and no resistance to the antibiotic has been reported to date. "Ramoplanin is more effective than frontline antibiotics such as vancomycin. In comparison to vancomycin, ramoplanin's relatively simplistic chemical architecture lends itself well to chemical synthesis and modification, qualities highly desirable for drug development,” said Dr. Dewey G. McCafferty, of the University of Pennsylvania (Philadelphia USA) and one of the authors. "More importantly, ramoplanin dodges the problems of antibiotic resistance by attacking the bacteria in a spot that cannot be easily overcome by normal mechanisms of mutational resistance.”

Bacteria treated with ramoplanin or vancomycin form weakened cell walls that spontaneously burst, killing the cell. The difference is where the two antibiotics interfere with peptidoglycan biosynthesis. Vancomycin binds to peptidoglycan monomers at the end of the peptide chain, where two D-alanine amino acid residues are found. Vancomycin resistant bacteria produce a competing peptidoglycan monomer with a mutation that reduces the ability of the antibiotic to bind. Ramoplanin, on the other hand, attaches itself to an essential sugar within the peptidoglycan molecule. This interaction is much less susceptible to the development of mutational resistance.

"Ramoplanin represents a genuinely new class of antimicrobial for the treatment of drug-resistant bacterial infections,” said Dr. McCafferty. "Our discovery of the molecular basis of its action will hopefully lead to the development of smaller, simplistic drugs derived from ramoplanin's structure with better antibiotic activity or more favorable biological properties.”




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