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: Tsuyoshi Yamamoto, Hidenori Matsui, Kenzaburo Yamaji, Tetsufumi Takahashi, Anders Øverby, Masahiko Nakamura, Atsuko Matsumoto, Kenichi Nonaka, Toshiaki Sunazuka, Satoshi Ōmura, Hirofumi Nakano
• Journal: Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (J Infect Chemother) Vol. 22 Issue 9 Pg. 587-92 (Sep 2016) ISSN: 1437-7780 [Electronic] Netherlands
• PMID: 27346378 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Intercellular Signaling Peptides and Proteins
• Nucleosides
• Peptides
• futalosine
• siamycin I
• Vitamin K 2
• Docosahexaenoic Acids
• Eicosapentaenoic Acid

Topics

• Animals
• Biosynthetic Pathways (drug effects)
• Docosahexaenoic Acids (antagonists & inhibitors, pharmacology)
• Drug Resistance, Bacterial (drug effects)
• Drug Therapy, Combination
• Eicosapentaenoic Acid (antagonists & inhibitors, pharmacology)
• Female
• Helicobacter Infections (drug therapy, prevention & control)
• Helicobacter pylori (drug effects, growth & development, isolation & purification, metabolism)
• Intercellular Signaling Peptides and Proteins
• Mice
• Mice, Inbred C57BL
• Nucleosides (biosynthesis)
• Peptides (antagonists & inhibitors, pharmacology)
• Vitamin K 2 (pharmacology)