3 research outputs found
Linearization of the Brevicidine and Laterocidine Lipopeptides Yields Analogues That Retain Full Antibacterial Activity
Brevicidine and laterocidine are macrocyclic lipodepsipeptides
with selective activity against Gram-negative bacteria, including
colistin-resistant strains. Previously, the macrocyclic core of these
peptides was thought essential for antibacterial activity. In this
study, we show that C-terminal amidation of linear brevicidine and
laterocidine scaffolds, and substitution of the native Thr9, yields
linear analogues that retain the potent antibacterial activity and
low hemolysis of the parent compounds. Furthermore, an alanine scan
of both peptides revealed that the aromatic and basic amino acids
within the common central scaffold are essential for antibacterial
activity. This linearization strategy for modification of cyclic peptides
is a highly effective way to reduce the time and cost of peptide synthesis
and may be applicable to other non-ribosomal antibacterial peptides
Linearization of the Brevicidine and Laterocidine Lipopeptides Yields Analogues That Retain Full Antibacterial Activity
Brevicidine and laterocidine are macrocyclic lipodepsipeptides
with selective activity against Gram-negative bacteria, including
colistin-resistant strains. Previously, the macrocyclic core of these
peptides was thought essential for antibacterial activity. In this
study, we show that C-terminal amidation of linear brevicidine and
laterocidine scaffolds, and substitution of the native Thr9, yields
linear analogues that retain the potent antibacterial activity and
low hemolysis of the parent compounds. Furthermore, an alanine scan
of both peptides revealed that the aromatic and basic amino acids
within the common central scaffold are essential for antibacterial
activity. This linearization strategy for modification of cyclic peptides
is a highly effective way to reduce the time and cost of peptide synthesis
and may be applicable to other non-ribosomal antibacterial peptides
Total Synthesis and Structure Assignment of the Relacidine Lipopeptide Antibiotics and Preparation of Analogues with Enhanced Stability
The unabated rise of antibiotic resistance has raised
the specter
of a post-antibiotic era and underscored the importance of developing
new classes of antibiotics. The relacidines are a recently discovered
group of nonribosomal lipopeptide antibiotics that show promising
activity against Gram-negative pathogens and share structural similarities
with brevicidine and laterocidine. While the first reports of the
relacidines indicated that they possess a C-terminal five-amino acid
macrolactone, an N-terminal lipid tail, and an overall positive charge,
no stereochemical configuration was assigned, thereby precluding a
full structure determination. To address this issue, we here report
a bioinformatics guided total synthesis of relacidine A and B and
show that the authentic natural products match our predicted and synthesized
structures. Following on this, we also synthesized an analogue of
relacidine A wherein the ester linkage of the macrolactone was replaced
by the corresponding amide. This analogue was found to possess enhanced
hydrolytic stability while maintaining the antibacterial activity
of the natural product in both in vitro and in vivo efficacy studies