Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2116-2118. doi: 10.1016/j.bmcl.2019.07.002. Epub 2019 Jul 2.

Abstract

The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1-10). Substituent effects ranged from σp = -0.27 to 0.78 for electronic and π = -0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn-1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.

Keywords: Beta-lactamase; BlaC; Inhibition; Phosphorylation; Tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Enzyme Assays
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Organophosphates / chemical synthesis
  • Organophosphates / chemistry*
  • Phosphorylation
  • Serine / chemistry
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors / chemical synthesis
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamases / chemistry*

Substances

  • Organophosphates
  • Small Molecule Libraries
  • beta-Lactamase Inhibitors
  • Serine
  • beta-Lactamases