Protein-DNA complex-guided discovery of the antibacterial lead E1 for restoring the susceptibility of Klebsiella Pneumoniae to polymyxin B by targeting the response regulator PmrA

Chem Commun (Camb). 2018 Jun 14;54(49):6372-6375. doi: 10.1039/c8cc01840e.

Abstract

A new antibacterial drug is urgently needed. We employed a protein-DNA complex-guided pharmacophore modeling approach to screen inhibitors against the response regulator PmrA of polymyxin B-resistant Klebsiella pneumoniae (KP). The identified lead, E1 (IC50 = 10.2 μM), targeted the DNA-binding domain of PmrA (KD = 1.7 μM), whose conserved residues R171, R198, K203, and Y214 have been shown to be hotspots for antimicrobial development. Treatment of E1 restored the susceptibility of KP to polymyxin B.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Benzenesulfonates / pharmacology*
  • DNA / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Drug Discovery*
  • Drug Resistance, Microbial / drug effects
  • Klebsiella pneumoniae / drug effects
  • Microbial Sensitivity Tests
  • Oxazoles / pharmacology*
  • Polymyxin B / pharmacology*
  • Protein Binding

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzenesulfonates
  • DNA-Binding Proteins
  • Oxazoles
  • pmrA protein, Bacteria
  • DNA
  • Polymyxin B