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Mechanism of Action of the Mannopeptimycins, a Novel Class of Glycopeptide Antibiotics Active against Vancomycin-Resistant Gram-Positive Bacteria

Alexey Ruzin,^* Guy Singh, Anatoly Severin, Youjun Yang, Russell G. Dushin, Alan G. Sutherland, Albert Minnick, Michael Greenstein, Michael K. May, David M. Shlaes, and Patricia A. Bradford

Wyeth Research, Pearl River, New York 10965

Received 10 July 2003/ Returned for modification 26 September 2003/ Accepted 22 November 2003

The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C₅₅-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.

Present address: Avon Products, Inc., Suffern, N.Y.

Present address: Idenix Pharmaceuticals, Cambridge, Mass.

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