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Antimicrobial Agents and Chemotherapy, August 2002, p. 2344-2348, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2344-2348.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Hexapeptide Derivatives of Glycopeptide Antibiotics: Tools for Mechanism of Action Studies

Norris E. Allen,^* Deborah L. LeTourneau, Joe N. Hobbs, Jr., and Richard C. Thompson

Infectious Diseases Research, Eli Lilly & Company, Indianapolis, Indiana 46285

Received 7 November 2001/ Returned for modification 12 February 2002/ Accepted 16 April 2002

Hexapeptide (des-N-methylleucyl) derivatives of LY264826 were prepared in order to examine further the role of N-substituted hydrophobic side chains in defining the mechanisms of action of semisynthetic glycopeptide antibiotics. The hexapeptide of LY264826 binds to the cell wall intermediate analog L-Lys-D-Ala-D-Ala with a 100-fold lower affinity than LY264826 and inhibits Micrococcus luteus almost 200-fold more poorly than LY264826 does. Alkylation of the 4-epi-vancosamine moiety of the disaccharide significantly enhanced the antibacterial activity of the hexapeptide. Alkylation did not affect the binding affinity for D-alanyl-D-alanine residues; however, it did enhance dimerization 7,000-fold and enhanced binding to bacterial membrane vesicles noticeably compared with the levels of dimerization and binding for the unsubstituted hexapeptide. The findings from this study complement those presented in an earlier report (N. E. Allen, D. L. LeTourneau, and J. N. Hobbs, Jr., J. Antibiot. 50:677-684, 1997) and are consistent with the conclusion that the enhanced antibacterial activities of semisynthetic glycopeptide antibiotics derive from the ability of the hydrophobic side chain to markedly affect both dimerization and binding to bacterial membranes.

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* Corresponding author. Present address: 1481 E. 77th St., Indianapolis, IN 46240. Phone: (317) 259-4933. Fax: (317) 277-4522. E-mail: norrisallen{at}comcast.net.

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Antimicrobial Agents and Chemotherapy, August 2002, p. 2344-2348, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2344-2348.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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