Mechanism and inhibition of the FabI enoyl-ACP reductase from Burkholderia pseudomallei

The Journal of Antimicrobial Chemotherapy
Nina LiuPeter J Tonge

Abstract

As an initial step in developing novel antibacterials against Burkholderia pseudomallei, we have characterized the FabI enoyl-ACP reductase homologues in the type II fatty acid biosynthesis pathway from this organism and performed an initial enzyme inhibition study. A BLAST analysis identified two FabI enoyl-ACP reductase homologues, bpmFabI-1 and bpmFabI-2, in the B. pseudomallei genome, which were cloned, overexpressed in Escherichia coli and purified. Steady-state kinetics was used to determine the reaction mechanism and the sensitivity of bpmFabI-1 to four diphenyl ether FabI inhibitors. The antibacterial activity of the inhibitors was assessed using a wild-type strain of Burkholderia thailandensis (E264) and an efflux pump mutant (Bt38). Consistent with its annotation as an enoyl-ACP reductase, bpmFabI-1 catalysed the NADH-dependent reduction of 2-trans-dodecenoyl-CoA via a sequential Bi Bi mechanism. In contrast, bpmFabI-2 was inactive with all substrates tested and only bpmfabI-1 was transcriptionally active under the growth conditions employed. The sensitivity of bpmFabI-1 to four diphenyl ethers was evaluated and in each case the compounds were slow-onset inhibitors with K(i) values of 0.5-2 nM. In addition, triclosan ...Continue Reading

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Citations

Jun 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Brian D AmesShiou-Chuan Tsai
Jan 25, 2016·Current Opinion in Microbiology·Sam J WillcocksBrendan W Wren
Sep 16, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry· YogiaraJae-Gu Pan
Sep 20, 2016·MedChemComm·Jesse A JonesKirk E Hevener
Nov 2, 2020·Bioorganic & Medicinal Chemistry Letters· YogiaraJae-Gu Pan

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