title: Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori.
abstract: We aimed to identify narrow-spectrum natural compounds that specifically inhibit an alternative menaquinone (MK; vitamin K2) biosynthetic pathway (the futalosine pathway) of Helicobacter pylori. Culture broth samples of 6183 microbes were examined using the paper disc method with different combinations of 2 of the following 3 indicator microorganisms: Bacillus halodurans C-125 and Kitasatospora setae KM-6054(T), which have only the futalosine pathway of MK biosynthesis, and Bacillus subtilis H17, which has only the canonical MK biosynthetic pathway. Most of the active compounds isolated from culture broth samples were from the families of polyunsaturated fatty acids (PUFAs). Only one compound isolated from the culture broth of Streptomyces sp. K12-1112, siamycin I (a 21-residue lasso peptide antibiotic), targeted the futalosine pathway. The inhibitory activities of representative PUFAs and siamycin I against the growth of B. halodurans or K. setae were abrogated by supplementation with MK. Thereafter, the growth of H. pylori strains SS1 and TN2GF4 in broth cultures was dose-dependently suppressed by eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or siamycin I, and these inhibitory effects were reduced by supplementation with MK. Daily administration of EPA (100 μM), DHA (100 μM), or siamycin I (2.5 μM) in drinking water reduced the H. pylori SS1 colonization in the gastric mucosa of C57BL/6 mice by 96%, 78%, and 68%, respectively. These data suggest that EPA, DHA, and siamycin I prevented H. pylori infection by inhibiting the futalosine pathway of MK biosynthesis.
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: hmatsui@lisci.kitasato-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Yamaji
authors.affiliation: Graduate School of Pharmaceutical Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Graduate School of Pharmaceutical Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Anders
authors.initials: A
authors.lastname: Øverby
authors.affiliation: Graduate School of Pharmaceutical Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nonaka
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakano
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004359:Drug Therapy, Combination; D015118:Eicosapentaenoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D016481:Helicobacter Infections / Q000188:drug therapy / Q000517:prevention & control*; D016480:Helicobacter pylori / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009705:Nucleosides / Q000096:biosynthesis*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D024482:Vitamin K 2 / Q000494:pharmacology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009705:Nucleosides; D010455:Peptides; C122040:futalosine; C094260:siamycin I; D024482:Vitamin K 2; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid
keywords: Alternative menaquinone biosynthetic pathway; Futalosine; Mouse infection model; Narrow-spectrum anti-Helicobacter pylori compounds; Polyunsaturated fatty acids; Siamycin I