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

Autor:	Kazuhisa Sekimizu, Takuya Kaji, Jyunichiro Yasukawa, Motoki Murai, Hiroshi Hamamoto, Masayuki Inoue, Hiroaki Itoh
Rok vydání:	2016
Předmět:	Staphylococcus aureus Stereochemistry 010402 general chemistry Peptides Cyclic 01 natural sciences Catalysis Structure-Activity Relationship chemistry.chemical_compound Solid-phase synthesis Cations Amide Moiety Guanidine Depsipeptide Molecular Structure 010405 organic chemistry Organic Chemistry Total synthesis General Chemistry Antimicrobial Combinatorial chemistry Anti-Bacterial Agents 0104 chemical sciences chemistry Antibacterial activity Hydrophobic and Hydrophilic Interactions
Zdroj:	Chemistry - A European Journal. 22:16912-16919
ISSN:	0947-6539
DOI:	10.1002/chem.201604022
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::970b6709d02de0b4655eafc699a41c00 https://doi.org/10.1002/chem.201604022 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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