title: Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis.
abstract: The first total synthesis of all six known A54556 acyldepsipeptide (ADEP) antibiotics from Streptomyces hawaiiensis is reported. This family of compounds has a unique mechanism of antibacterial action, acting as activators of caseinolytic protease (ClpP). Assembly of the 16-membered depsipeptide core was accomplished via a pentafluorophenyl ester-based macrolactamization strategy. Late stage amine deprotection was carried out under neutral conditions by employing a mild hydrogenolysis strategy, which avoids the formation of undesired ring-opened depsipeptide side products encountered during deprotection of acid-labile protecting groups. The free amines were found to be significantly more reactive toward late stage amide bond formation as compared to the corresponding ammonium salts, giving final products in excellent yields. A thorough NMR spectroscopic analysis of these compounds was carried out to formally assign the structures and to aid with the spectroscopic assignment of ADEP analogues. The identity of two of the structures was confirmed by comparison with biologically produced samples from S. hawaiiensis. An X-ray crystallographic analysis of an ADEP analogue reveals a conformation similar to that found in cocrystal structures of ADEPs with ClpP protease. The degree of antibacterial activity of the different compounds was evaluated in vitro using MIC assays employing both Gram-positive and Gram-negative strains and a fluorescence-based biochemical assay.
authors.affiliation: Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, ON M5S 3H6, Canada.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Goodreid
authors.forename: Keith
authors.initials: K
authors.lastname: Wong
authors.forename: Elisa
authors.initials: E
authors.lastname: Leung
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McCaw
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
authors.forename: Alan
authors.initials: A
authors.lastname: Lough
authors.forename: Walid A
authors.initials: WA
authors.lastname: Houry
authors.forename: Robert A
authors.initials: RA
authors.lastname: Batey
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049071:Endopeptidase Clp; D029968:Escherichia coli Proteins / Q000819:agonists; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009345:Neisseria meningitidis / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D029968:Escherichia coli Proteins; C483572:ClpP protease, E coli; D049071:Endopeptidase Clp