A significantly enhanced antibacterial spectrum of D-enantiomeric lipopeptide bactenecin

• Published in: Biochemical and biophysical research communications Vol. 514; no. 2; pp. 497 - 502
• Main Authors: Sim, Ji-Yeong, Kim, Shanghyeon, Lee, Jaeho, Lim, Hyunjung, Kim, Ha Hyung, Park, Zee-Yong, Kim, Jae Il
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.06.2019
• Subjects: Antibacterial activity; Bactenecin analog; D-enantiomeric lipopeptide; Fatty acid conjugation; PBS; KCCM; KCTC; MIC; Fatty acid conjugation; ATCC; RP-HPLC; MALDI-TOF MS; CCARM; ONPG; POPG; POPC; FE-SEM; Antibacterial activity; Bactenecin analog; hRBC; CAMP; D-enantiomeric lipopeptide; ELISA
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.04.153

Cationic antimicrobial peptides (CAMPs) are important antibiotics because they possess a broad spectrum of activity against both Gram-positive and Gram-negative bacteria, including those resistant to traditional antibiotics. The cyclic peptide bactenecin is a 12-amino acid CAMP that contains one intramolecular disulfide bond. To improve the antibacterial activity of bactenecin, we designed and synthesized several bactenecin analogs by applying multiple approaches, including amino acid substitution, use of the d-enantiomeric form, and lipidation. Among the synthetic analogs, d-enantiomeric bactenecin conjugated to capric acid, which we named dBacK-(cap), exhibited a significantly enhanced antibacterial spectrum with MIC values ranging from 1 to 8 μM against both Gram-positive and Gram-negative bacteria, including some drug-resistant bacteria. Upon exposure to dBacK-(cap), S. aureus cells were killed within 1 h at the MIC value, but full inactivation of E. coli required over 2 h. These results indicate that covalent addition of a d-amino acid and a fatty acid to bactenecin is the most effective approach for enhancing its antibacterial activity. •dBacK-(cap) was designed via a combination of amino acid substitution, incorporation of d-amino acids, and lipidation.•dBacK-(cap) showed potent antibacterial activity against all of the tested Gram-positive and Gram-negative bacteria.•dBacK-(cap) exhibited rapid killing kinetics and potent membrane permeabilization ability against the bacterial strains.