Biochemical and biophysical research communications | 2019
A significantly enhanced antibacterial spectrum of D-enantiomeric lipopeptide bactenecin.
Abstract
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\u202fμM against both Gram-positive and Gram-negative bacteria, including some drug-resistant bacteria. Upon exposure to dBacK-(cap), S.\xa0aureus cells were killed within 1\u202fh\u202fat the MIC value, but full inactivation of E.\xa0coli required over 2\u202fh. 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.