title: A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity.
abstract: Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Barcelona.
authors.forename: Francesc
authors.initials: F
authors.lastname: Rabanal
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Barcelona.
authors.forename: Ariadna
authors.initials: A
authors.lastname: Grau-Campistany
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), Hospital Clínic - University of Barcelona.
authors.forename: Xavier
authors.initials: X
authors.lastname: Vila-Farrés
authors.affiliation: Experimental Toxicology and Ecotoxicology Unit /CERETOX, Barcelona Science Park.
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez-Linares
authors.affiliation: Experimental Toxicology and Ecotoxicology Unit /CERETOX, Barcelona Science Park.
authors.forename: Miquel
authors.initials: M
authors.lastname: Borràs
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), Hospital Clínic - University of Barcelona.
authors.forename: Jordi
authors.initials: J
authors.lastname: Vila
authors.affiliation: Laboratory of Microbiology, Faculty of Pharmacy, University of Barcelona.
authors.forename: Angeles
authors.initials: A
authors.lastname: Manresa
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Cajal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D004285:Dogs; D024901:Drug Resistance, Multiple, Bacterial; D005347:Fibroblasts; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000648:ultrastructure; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D020128:Inhibitory Concentration 50; D055666:Lipopeptides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D055666:Lipopeptides; D010456:Peptides, Cyclic