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Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens

Adam D Tomich1, Erik H Klontz2,3, Daniel Deredge4

  • 1Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Antimicrobial Agents and Chemotherapy
|January 16, 2019
PubMed

Insights

A new inhibitor, ANY1, targets the FosA enzyme, which confers resistance to the antibiotic fosfomycin (FOM) in Gram-negative bacteria. This discovery offers a strategy to restore FOM

Area of Science:

  • Microbiology
  • Drug Discovery
  • Biochemistry

Background:

  • Multidrug-resistant Gram-negative bacteria pose a significant public health threat.
  • Existing antibiotic development pipelines are insufficient to combat rising resistance.
  • Fosfomycin (FOM) is effective against some Gram-negative bacteria but not others, like Klebsiella pneumoniae and Pseudomonas aeruginosa, due to the FosA enzyme.

Purpose of the Study:

  • To discover and characterize a small-molecule inhibitor of the FosA enzyme.
  • To develop a strategy to expand the activity spectrum of fosfomycin.

Main Methods:

  • Discovery and characterization of ANY1, a small-molecule inhibitor of FosA.
  • Biochemical and structural analysis of ANY1's interaction with FosA.
  • Testing ANY1's ability to potentiate FOM activity in Gram-negative pathogens.

Main Results:

  • ANY1 was identified as an active-site inhibitor of the FosA enzyme.
  • ANY1 was biochemically and structurally characterized.
  • ANY1 demonstrated potentiation of FOM activity in Gram-negative pathogens, including resistant strains.

Conclusions:

  • ANY1 represents a novel strategy to overcome FosA-mediated fosfomycin resistance.
  • This approach can broaden the utility of fosfomycin against a wider range of Gram-negative pathogens.
  • The findings offer a new therapeutic avenue for treating multidrug-resistant infections.
Keywords:
FosAGram negativefosfomycin

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