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J. Biol. Chem., Vol. 279, Issue 35, 36250-36258, August 27, 2004

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Novel Lipoglycopeptides as Inhibitors of Bacterial Signal Peptidase I^*

Palaniappan Kulanthaivel, Adam J. Kreuzman, Mark A. Strege, Matthew D. Belvo, Tim A. Smitka, Matthew Clemens, James R. Swartling, Kristina L. Minton, Feng Zheng, Eddie L. Angleton, Deborah Mullen, Louis N. Jungheim, Valentine J. Klimkowski, Thalia I. Nicas, Richard C. Thompson, and Sheng-Bin Peng

From the Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Signal peptidase (SPase) I is responsible for the cleavage of signal peptides of many secreted proteins in bacteria. Because of its unique physiological and biochemical properties, it serves as a potential target for development of novel antibacterial agents. In this study, we report the production, isolation, and structure determination of a family of structurally related novel lipoglycopeptides from a Streptomyces sp. as inhibitors of SPase I. Detailed spectroscopic analyses, including MS and NMR, revealed that these lipoglycopeptides share a common 14-membered cyclic peptide core, an acyclic tripeptide chain, and a deoxy--mannose sugar, but differ in the degree of oxidation of the N-methylphenylglycine residue and the length and branching of the fatty acyl chain. Biochemical analysis demonstrated that these peptides are potent and competitive inhibitors of SPase I with K_i 50 to 158 nM. In addition, they showed modest antibacterial activity against a panel of pathogenic Gram-positive and Gram-negative bacteria with minimal inhibitory concentration of 8–64 µM against Streptococcus pneumonniae and 4–8 µM against Escherichia coli. Notably, they mechanistically blocked the protein secretion in whole cells as demonstrated by inhibiting -lactamase release from Staphylococcus aureus. Taken together, the present discovery of a family of novel lipoglycopeptides as potent inhibitors of bacterial SPase I may lead to the development of a novel class of broad-spectrum antibiotics.

Received for publication, May 26, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. Tel.: 317-433-4549; Fax: 317-276-1414; E-mail: Peng_Sheng-Bin{at}Lilly.com.

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