2. Academic Validation
  3. Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

  • J Med Chem. 2016 Jan 28;59(2):624-46. doi: 10.1021/acs.jmedchem.5b01451.
Jordan D Goodreid 1,  John Janetzko 2 3,  John P Santa Maria Jr 2,  Keith S Wong 4,  Elisa Leung 4,  Bryan T Eger 4,  Steve Bryson 4 5,  Emil F Pai 4 6 7 5,  Scott D Gray-Owen 6,  Suzanne Walker 2,  Walid A Houry 4,  Robert A Batey 1
Affiliations

Affiliations

  • 1 Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
  • 2 Department of Microbiology and Immunobiology, Harvard Medical School , Boston, Massachusetts 02115, United States.
  • 3 Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
  • 4 Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
  • 5 The Campbell Family Institute for Cancer Research, University Health Network , Toronto, Ontario M5G 1L7, Canada.
  • 6 Department of Molecular Genetics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
  • 7 Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
PMID: 26818454 DOI: 10.1021/acs.jmedchem.5b01451
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.

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