title: An Acyl-Linked Dimer of Daptomycin Is Strongly Inhibited by the Bacterial Cell Wall.
abstract: The lipopeptide antibiotic daptomycin is active against Gram-positive pathogens. It permeabilizes bacterial cell membranes, which involves the formation of membrane-associated oligomers. We here studied a dimer of daptomycin whose two subunits were linked through a bivalent aliphatic acyl chain. Unexpectedly, the dimer had very low activity on vegetative Staphylococcus aureus and Bacillus subtilis cells. However, activity resembled that of monomeric daptomycin on liposomes and on B. subtilis L-forms. These findings underscore the importance of the bacterial cell wall in daptomycin resistance.
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Bradley
authors.initials: B
authors.lastname: Scott
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Michael
authors.identifier: 0000-0003-0956-8498
authors.initials: M
authors.lastname: Palmer
mesh_terms: D000215:Acylation; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D001692:Biological Transport; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D017576:Daptomycin / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry; D019281:Dimerization; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D008081:Liposomes / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D010539:Permeability; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013229:Stearic Acids / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D003998:Dicarboxylic Acids; D008081:Liposomes; D013229:Stearic Acids; C010266:octadecane-1,18-dioic acid; D017576:Daptomycin
keywords: antibiotic resistance; bacterial L-forms; cell wall permeability; lipopeptide antibiotics