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GPCRs Regulate Adenylyl Cylase Activity01:09

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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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Ureadepsipeptides as ClpP Activators.

Elizabeth C Griffith1, Ying Zhao1, Aman P Singh1

  • 1Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , 262 Danny Thomas Place , Memphis , Tennessee 38105 , United States.

ACS Infectious Diseases
|October 8, 2019
PubMed
Summary
This summary is machine-generated.

New ureadepsipeptides activate bacterial ClpP protease, offering a promising strategy against antibiotic-resistant Staphylococcus aureus biofilms. These compounds show improved metabolic stability and potent antibacterial activity.

Keywords:
ClpPacyldepsipeptideantibioticbiofilmureadepsipeptide

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Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Acyldepsipeptides are antibiotics targeting bacterial caseinolytic protease (ClpP), effective against non-growing bacteria and biofilms.
  • The rapid metabolism of the acyldepsipeptide scaffold limits its therapeutic potential.
  • Targeting ClpP offers a novel approach to combat challenging biofilm infections.

Purpose of the Study:

  • To develop novel ClpP activators with enhanced metabolic stability.
  • To investigate the structure-activity relationship of modified acyldepsipeptide analogs.
  • To explore new therapeutic strategies against Staphylococcus aureus biofilms.

Main Methods:

  • Targeted synthesis of phenyl urea-substituted depsipeptides (ureadepsipeptides).
  • Assessment of ClpP activation potency in Staphylococcus aureus.
  • Evaluation of antibacterial activity against Gram-positive bacteria and biofilms.
  • Structural studies to elucidate binding interactions.

Main Results:

  • A new class of ureadepsipeptides with improved metabolic stability was synthesized.
  • Ureadepsipeptides are potent activators of Staphylococcus aureus ClpP.
  • These compounds exhibit significant activity against Staphylococcus aureus biofilms.
  • The phenyl urea motif mimics the essential double bond, maintaining potency while reducing metabolic liability.

Conclusions:

  • Ureadepsipeptides represent a novel class of ClpP activators with improved drug-like properties.
  • The phenyl urea moiety confers metabolic stability and retains antibacterial potency.
  • These compounds offer a promising new avenue for developing treatments against biofilm infections.