title: Effects of cyclic lipodepsipeptide structural modulation on stability, antibacterial activity, and human cell toxicity.
abstract: Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections by drug-resistant bacteria is of vital importance. The structurally simple yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We synthesized 18 fusaricidin/LI-F analogues and investigated the effects of structure modification on their conformation, serum stability, antibacterial activity, and toxicity toward human cells. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogues with improved stability and greatly decreased cytotoxicity. The lower overall hydrophobicity/amphiphilicity of amide analogues in comparison with their parent depsipeptides, as indicated by HPLC retention times, may explain the dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogues may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogues as lead structures for the development of new antibacterial agents.
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Bionda
authors.forename: Maciej
authors.initials: M
authors.lastname: Stawikowski
authors.forename: Roma
authors.initials: R
authors.lastname: Stawikowska
authors.forename: Maré
authors.initials: M
authors.lastname: Cudic
authors.forename: Fabian
authors.initials: F
authors.lastname: López-Vallejo
authors.forename: Daniela
authors.initials: D
authors.lastname: Treitl
authors.forename: José
authors.initials: J
authors.lastname: Medina-Franco
authors.forename: Predrag
authors.initials: P
authors.lastname: Cudic
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic