Total Synthesis of LL-A0341β.

The first total synthesis of cyclic depsipeptide antibiotic LL-A0341β (LL) is described. The configuration of the β-methyltryptophan (β-MeTrp) residue was established by preparing all four stereoisomers of Fmoc-β-MeTrp which were used for the synthesis of LL via Fmoc solid phase peptide synthesis. The most active of the four peptides was the one containing (2,3)-β-MeTrp.

The Calcium-Dependent Antibiotics: Structure-Activity Relationships and Determination of Their Lipid Target.

The calcium-dependent antibiotics (CDAs) are a group of seven closely related membrane-active cyclic lipopeptide antibiotics (cLPAs) first isolated in the early 1980s from the fermentation broth of . Their target was unknown, and the mechanism of action is uncertain. Herein, we report new routes for the synthesis of CDA4b and its analogues, explore the structure-activity relationships at its lipid tail and at positions 3, 9, and 11, and determine the CDAs' lipid target.

Effect of Lipid Length and Cationic Residues on the Antibacterial and Hemolytic Activities of Paenibacterin.

Paenibacterin A1 (PA1) is a broad-spectrum, cationic cyclic lipodepsipeptide antibiotic isolated from . In this study, the roles of the cationic residues and lipid tail length on the in vitro antibacterial and hemolytic activities of PA1 was examined in the context of an active PA1 analogue, called PAK, in which the two D-Orn residues in PA1 were converted to D-Lys residues. The effect of reducing the length of the lipid tail in PAK from 15 to 12-10 carbons on the minimum inhibitory concentration (MIC) depended upon the bacteria.

Discovery of Highly Active Derivatives of Daptomycin by Assessing the Effect of Amino Acid Substitutions at Positions 8 and 11 on a Daptomycin Analogue.

Daptomycin is an important antibiotic used for treating serious infections caused by Gram-positive bacteria including methicillin-resistant (MRSA) and vancomycin-resistant enterococci. Establishing structure-activity relationships of daptomycin is important for developing new daptomycin-based antibiotics with expanded clinical applications and for tackling the ever-increasing problem of antimicrobial resistance. Toward this end, Dap-K6-E12-W13, an active analogue of daptomycin in which the uncommon amino acids in daptomycin are replaced with their common counterparts, was used as a model system for studying the effect of amino acid variation at positions 8 and 11 on in vitro biological activity against a model organism, , and calcium-dependent insertion into model membranes.