Structure-activity relationship of daptomycin analogues with substitution at (2S, 3R) 3-methyl glutamic acid position

Bioorg Med Chem Lett. 2017 Feb 1;27(3):456-459. doi: 10.1016/j.bmcl.2016.12.046. Epub 2016 Dec 18.

Abstract

Daptomycin is a highly effective lipopeptide antibiotic against Gram-positive pathogens. The presence of (2S, 3R) 3-methyl glutamic acid (mGlu) in daptomycin has been found to be important to the antibacterial activity. However the role of (2S, 3R) mGlu is yet to be revealed. Herein, we reported the syntheses of three daptomycin analogues with (2S, 3R) mGlu substituted by (2S, 3R) methyl glutamine (mGln), dimethyl glutamic acid and (2S, 3R) ethyl glutamic acid (eGlu), respectively, and their antibacterial activities. The detailed synthesis of dimethyl glutamic acid was also reported.

Keywords: Antibiotics; Daptomycin; Methyl glutamic acid; Solid phase peptide synthesis; Structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Daptomycin / analogs & derivatives*
  • Daptomycin / chemical synthesis
  • Daptomycin / pharmacology
  • Glutamic Acid / chemistry*
  • Microbial Sensitivity Tests
  • Staphylococcus aureus / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Glutamic Acid
  • Daptomycin