The contribution of achiral residues in the laspartomycin family of calcium-dependent lipopeptide antibiotics

Abstract

The three glycine residues present in the laspartomycin macrocycle demonstrate different tolerances to substitution.

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

“…Position 6 plays a key role in the calcium-binding motif (Asp 5 -X 6 -Asp 7 -Gly 8 ), and its substitution plays a significant role in the antibacterial activity of the antibiotic molecule ( Strieker and Marahiel, 2009 ). Daptomycin contains alanine at position 6 ( Wood et al, 2019 ), whereas 5812-A/C contains leucine as was determined preliminarily. This might explain a certain difference in calcium-dependent bactericidal activity between daptomycin and 5812-A/C.…”

“…Binding of calcium is almost exclusively coordinated in proteins by oxygen ligands that originate in the side-chain carboxyl groups of Asp and Glu ( Kirberger and Yang, 2013 ). Calcium-dependent antibiotics usually contain conserved Asp 5 -X 6 -Asp 7 -Gly 8 calcium-binding motifs ( Strieker and Marahiel, 2009 ; Wood et al, 2019 ). As was established by the Edman amino acid sequencing, 5812-A/C has a similar motif in the sequence Leu- Asp-Gly -Ser-Gly.…”

A Convenient Chemoenzymatic Preparation of Chimeric Macrocyclic Peptide Antibiotics with Potent Activity against Gram-Negative Pathogens

“…Following selective allyl ester removal and cleavage from the resin, the BamA-targeting macrocycle is subsequently formed in solution followed by global deprotection to yield the desired bicyclic conjugate 3 . Given our interest in macrocyclic peptide antibiotics and semisynthesis, − we were drawn to explore alternative strategies for the preparation of these constructs. Specifically, rather than synthesizing the PMEN motif “from scratch”, we considered a chemoenzymatic approach involving degradation of readily available colistin followed by coupling to the BamA-targeting macrocycle.…”

Mechanistic insights into the C55-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures

“…To evaluate the impact of introducing amino acids specic to the friulimicins/amphomycin class into laspartomycin C we applied a exible synthetic route wherein the linear peptide precursor, including the N-terminal lipid, was rst assembled on solid support using the acid sensitive 2-chlorotrityl resin (Scheme 1). 11,21,22 Notably, Gly residues at positions 6 and 8 were incorporated using the corresponding Fmoc-DMB-Gly building block to avoid aspartamide formation. On resin removal of the Alloc group on the Dap2 side chain was followed by mild acid cleavage to yield the protected linear peptide intermediate.…”