title: Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II.
abstract: Flavonoids comprise a large group of bioactive polyphenolic plant secondary metabolites. Several of these possess potent in vivo activity against Escherichia coli and Plasmodium falciparum, targeting enzymes involved in fatty acid biosynthesis, such as enoyl-ACP-reductase, beta-ketoacyl-ACP reductase and beta-hydroxyacyl-ACP dehydratase. Herein, we report that butein, isoliquirtigenin, 2,2',4'-trihydroxychalcone and fisetin inhibit the growth of Mycobacterium bovis BCG. Furthermore, in vitro inhibition of the mycolic-acid-producing fatty acid synthase II (FAS-II) of Mycobacterium smegmatis suggests a mode of action related to those observed in E. coli and P. falciparum. Through a bioinformatic approach, we have established the product of Rv0636 as a candidate for the unknown mycobacterial dehydratase, and its overexpression in M. bovis BCG conferred resistance to growth inhibition by butein and isoliquirtigenin, and relieved inhibition of fatty acid and mycolic acid biosynthesis in vivo. Furthermore, after overexpression of Rv0636 in M. smegmatis, FAS-II was less sensitive to these inhibitors in vitro. Overall, the data suggest that these flavonoids are inhibitors of mycobacterial FAS-II and in particular Rv0636, which represents a strong candidate for the beta-hydroxyacyl-ACP dehydratase enzyme of M. tuberculosis FAS-II.
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Alistair K
authors: AK
authors: Brown
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Athina
authors: A
authors: Papaemmanouil
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Veemal
authors: V
authors: Bhowruth
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Apoorva
authors: A
authors: Bhatt
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Lynn G
authors: LG
authors: Dover
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Gurdyal S
authors: GS
authors: Besra
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D047188:Chalcones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D016415:Sequence Alignment
chemical_list: D000900:Anti-Bacterial Agents; D047188:Chalcones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D044948:Flavonols; C040918:butein; C040920:isoliquiritigenin; D006836:Hydro-Lyases; C036180:beta-hydroxyacyl-(acyl-carrier-protein)dehydrase; D054889:Fatty Acid Synthase, Type II; C017875:fisetin