Abstract
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 (
). In agreement with the original isolation paper, pleasingly, synthetic
demonstrated antimicrobial activity toward
,
, and
(MIC = 4-8 μgmL
). Interestingly, however, synthetic
was inactive toward all of the tested Gram-positive pathogens, including methicillin-resistant
strains. Substitution of d-Phe
with its enantiomer, and other hydrophobic residues, yields analogues that were either inactive or only exhibited activity toward Gram-negative strains. The striking difference in the biological activity of our synthetic
compared to the reported natural compound warrants the re-evaluation of the original natural product for purity or possible differences in relative configuration. Finally, the evaluation of synthetic
and
in a human kidney organoid model of nephrotoxicity revealed substantial toxicity of both compounds, although
was less toxic than
and polymyxin B. These results indicate that modification to position 2 may afford a strategy to mitigate the nephrotoxicity of brevicidine.