Synthesis, Structure-Activity Relationship Study, Bioactivity, and Nephrotoxicity Evaluation of the Proposed Structure of the Cyclic Lipodepsipeptide Brevicidine B.

The brevicidines represent a novel class of nonribosomal antimicrobial peptides that possess remarkable potency and selectivity toward highly problematic and resistant Gram-negative pathogenic bacteria. A recently discovered member of the brevicidine family, coined brevicidine B (), comprises a single amino acid substitution (from d-Tyr to d-Phe) in the amino acid sequence of the linear moiety of brevicidine () and was reported to exhibit broader antimicrobial activity against both Gram-negative (MIC = 2-4 μgmL) and Gram-positive (MIC = 2-8 μgmL) pathogens. Encouraged by this, we herein report the first total synthesis of the proposed structure of brevicidine B (), building on our previously reported synthetic strategy to access brevicidine ().

Factors influencing on-resin depsipeptide bond formation: case studies on daptomycin- and brevicidine-derived sequences.

Depsipeptides are an important class of bioactive natural products, where a growing number of genome-mined structures that display anti-microbial activity are macrocyclic depsipeptides. Chemically, peptide ester (depsipeptide) bond formation often displays low yields, and thereby hampers efforts to access these structures for structure-activity studies. Herein, we present a systematic study of the variables that influence depsipeptide bond formation on-resin, using simplified sequences derived from antibiotic peptides, daptomycin and brevicidine, prepared Fmoc-based solid-phase synthesis.

The Total Chemical Synthesis and Biological Evaluation of the Cationic Antimicrobial Peptides, Laterocidine and Brevicidine.

Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from through a global genome-mining approach. Both laterocidine and brevicidine exhibit potent antimicrobial activity toward Gram-negative bacteria, including difficult-to-treat and colistin-resistant , and a low risk of resistance development.