Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity

Takuya Kaji, Motoki Murai, Hiroaki Itoh, Jyunichiro Yasukawa, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Lysocin E (1) is a structurally complex 37-membered depsipeptide comprising 12 amino-acid residues with an N-methylated amide and an ester linkage. Compound 1 binds to menaquinone (MK) in the bacterial membrane to exert its potent bactericidal activity. To decipher the biologically important functionalities within this unique antibiotic, we performed a comprehensive structure-activity relationship (SAR) study by systematically changing the side-chain structures of l-Thr-1, d-Arg-2, N-Me-d-Phe-5, d-Arg-7, l-Glu-8, and d-Trp-10. First, we achieved total synthesis of the 14 new side-chain analogues of 1 by employing a solid-phase strategy. We then evaluated the MK-dependent liposomal disruption and antimicrobial activity against Staphylococcus aureus by 1 and its analogues. Correlating data between the liposome and bacteria experiments revealed that membrane lysis was mainly responsible for the antibacterial functions. Altering the cationic guanidine moiety of d-Arg-2/7 to a neutral amide, and the C7-acyl group of l-Thr-1 to the C2 or C11 counterpart decreased the antimicrobial activities four- or eight-fold. More drastically, chemical mutation of d-Trp-10 to d-Ala-10 totally abolished the bioactivities. These important findings led us to propose the biological roles of the side-chain functionalities.

Original languageEnglish
Pages (from-to)16912-16919
Number of pages8
JournalChemistry - A European Journal
Volume22
Issue number47
DOIs
Publication statusPublished - 2016 Nov 14
Externally publishedYes

Keywords

  • antibiotics
  • peptides
  • solid-phase synthesis
  • structure-activity relationships
  • total synthesis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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