Inhibition of Mycobacterium tuberculosis InhA by 3-nitropropanoic acid

Proteins. 2022 Mar;90(3):898-904. doi: 10.1002/prot.26268. Epub 2021 Oct 28.

Abstract

3-Nitropropanoic acid (3NP), a bioactive fungal natural product, was previously demonstrated to inhibit growth of Mycobacterium tuberculosis. Here we demonstrate that 3NP inhibits the 2-trans-enoyl-acyl carrier protein reductase (InhA) from Mycobacterium tuberculosis with an IC50 value of 71 μM, and present the crystal structure of the ternary InhA-NAD+ -3NP complex. The complex contains the InhA substrate-binding loop in an ordered, open conformation with Tyr158, a catalytically important residue whose orientation defines different InhA substrate/inhibitor complex conformations, in the "out" position. 3NP occupies a hydrophobic binding site adjacent to the NAD+ cofactor and close to that utilized by the diphenyl ether triclosan, but binds predominantly via electrostatic and water-mediated hydrogen-bonding interactions with the protein backbone and NAD+ cofactor. The identified mode of 3NP binding provides opportunities to improve inhibitory activity toward InhA.

Keywords: 3-nitropropanoic acid; InhA; Mycobacterium tuberculosis; antituberculosis; bioactive compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / antagonists & inhibitors*
  • Binding Sites
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Mycobacterium tuberculosis / chemistry*
  • NAD / chemistry
  • Nitro Compounds / chemistry*
  • Oxidoreductases / antagonists & inhibitors*
  • Phenyl Ethers / chemistry
  • Propionates / chemistry*
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Bacterial Proteins
  • Nitro Compounds
  • Phenyl Ethers
  • Propionates
  • NAD
  • phenyl ether
  • Oxidoreductases
  • InhA protein, Mycobacterium
  • 3-nitropropionic acid