Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. Academic Article uri icon


  • The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.

published proceedings

  • J Biol Chem

altmetric score

  • 3

author list (cited authors)

  • Perozzo, R., Kuo, M., Sidhu, A., Valiyaveettil, J. T., Bittman, R., Jacobs, W. R., Fidock, D. A., & Sacchettini, J. C.

citation count

  • 168

complete list of authors

  • Perozzo, Remo||Kuo, Mack||Sidhu, Amar bir Singh||Valiyaveettil, Jacob T||Bittman, Robert||Jacobs, William R||Fidock, David A||Sacchettini, James C

publication date

  • April 2002