Branched fatty acids inhibit the biosynthesis of menaquinone in Helicobacter pylori

Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori

“…Thus, 5'-methylthioadenosine nucleosidase was found to play a key role in the futalosine pathway of H. pylori (i.e., chorismate / 6-amino-6-deoxyfutalosine / dehypoxanthinyl futalosine / cyclic dehypoxantine futalosine / 1,4-dihydroxy-6-naphthoic acid / MK) [29,30]. FAs have been shown to possibly inhibit a step after the formation of futalosine [24]. Indeed, several FAs have inhibitory effects on H. pylori growth in vitro [28,31].…”

“…Paper discs (6 mm diameter; Advantec, Tokyo) containing test samples were placed on agar plates seeded with different combinations of 2 of the following 3 indicator microorganisms: Bacillus halodurans C-125 [24] and Kitasatospora setae KM-6054 T [25,26], which have only the futalosine pathway of MK biosynthesis, and Bacillus subtilis H17 (a gift from Dr. T. Kada of the National Institute of Genetics, Japan), which has only the canonical MK biosynthetic pathway [24]. K. setae KM-6054 T (1 Â 10 4 spores/ mL), B. halodurans C-125 (2 Â 10 2 spores/mL), or B. subtilis H17 (2 Â 10 2 spores/mL) was grown on 1.0% (w/v) agar plates containing 1.0% (w/v) glucose and 1.0% (w/v) yeast extract for 24 h at 27 C, 1.5% (w/v) agar plates containing 1.7% (w/v) tryptone, 0.3% (w/v) soytone, 0.25% (w/v) dextrose, 0.5% (w/v) sodium chloride, and 0.25% (w/v) K 2 HPO 4 for 24 h at 37 C, or 0.8% (w/v) agar plates containing 0.5% (w/v) yeast extract, 0.5% (w/v) polypeptone, 2.0% (w/v) sodium chloride, 20 mg/L L-tryptophan, 20 mg/L L-arginine, and 1 mg/L phenol red for 15 h at 37 C, respectively.…”

Identification of self-growth-inhibiting compounds lauric acid and 7-(Z)-tetradecenoic acid from Helicobacter pylori

“…This evidence suggested that an n-3 polyunsaturated fatty acid impaired the interaction between H. pylori and gastric epithelial cells. Tanaka et al (2011) demonstrated that branched fatty acids inhibit the biosynthesis of menaquinone, which is an essential component of the electron transfer pathway in H. pylori.…”

Identification of tirandamycins as specific inhibitors of the futalosine pathway

“…Although it remains unclear how tirandamycins specifically inhibit an enzyme in the futalosine pathway, the molecular recognition of the enzymes, possibly due to subtle differences in the substrates, may be important to distinguish the two pathways of MK biosynthesis. 7 To date, several compounds including branched fatty acids 8 , polyunsaturated fatty acids 15 , a lasso peptide siamycin I 15 , and a transition state analog of nucleosidases (BuTDADMe-ImmA) 16 , have been identified as specific inhibitors targeting the futalosine pathway. It had been proposed that branched fatty acids and polyunsaturated fatty acids inhibited an enzyme that catalyzes the transfer of a prenyl side chain to the naphthoquinone moiety.…”

“…To identify compounds that specifically inhibit the futalosine pathway, we employed a previously developed screening method. 8 For the initial screening, we used the paper disk method and employed two closely related Bacillus strains, Bacillus subtilis strain 168 and 3 Bacillus halodurans C-125, as the test organisms. By genome sequencing, these two strains had been shown to possess a high degree of similarity.…”