title: Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity.
abstract: The problem of antibiotic resistance has prompted the search for new antibiotics with novel mechanisms of action. Analogues of the A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class of antimicrobial agents that act through dysregulation of caseinolytic protease (ClpP). Previous studies have shown that ADEPs are active against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there are currently few studies examining Gram-negative bacteria. In this study, the synthesis and biological evaluation of 14 novel ADEPs against a variety of pathogenic Gram-negative and Gram-positive organisms is outlined. Optimization of the macrocyclic core residues and N-acyl side chain culminated in the development of 26, which shows potent activity against the Gram-negative species Neisseria meningitidis and Neisseria gonorrheae and improved activity against the Gram-positive organisms Staphylococcus aureus and Enterococcus faecalis in comparison with known analogues. In addition, the co-crystal structure of an ADEP-ClpP complex derived from N. meningitidis was solved.
authors.affiliation: Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Goodreid
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: John
authors.initials: J
authors.lastname: Janetzko
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Santa Maria
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leung
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Eger
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.|The Campbell Family Institute for Cancer Research, University Health Network , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Bryson
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.|Department of Molecular Genetics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.|Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.|The Campbell Family Institute for Cancer Research, University Health Network , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Department of Molecular Genetics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Walid A
authors.initials: WA
authors.lastname: Houry
authors.affiliation: Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Batey
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002364:Caseins / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002364:Caseins; D010447:Peptide Hydrolases