New Antibiotic Candidates against Helicobacter pylori

Shanzhi Wang, Scott A. Cameron, Keith Clinch, Gary B. Evans, Zhimeng Wu, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the worlds population. It is responsible for most peptic ulcers and is an important risk factor for gastric cancer. Antibiotic treatment for H. pylori infections is challenging as drug resistance has developed to antibiotics with traditional mechanisms of action. H. pylori uses an unusual pathway for menaquinone biosynthesis with 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzing an essential step. We validated MTAN as a target with a transition-state analogue of the enzyme [Wang, S.; Haapalainen, A. M.; Yan, F.; et al. Biochemistry 2012, 51, 6892-6894]. MTAN inhibitors will only be useful drug candidates if they can both include tight binding to the MTAN target and have the ability to penetrate the complex cell membrane found in Gram-negative H. pylori. Here we explore structural scaffolds for MTAN inhibition and for growth inhibition of cultured H. pylori. Sixteen analogues reported here are transition-state analogues of H. pylori MTAN with dissociation constants of 50 pM or below. Ten of these prevent growth of the H. pylori with IC90 values below 0.01 μg/mL. These remarkable compounds meet the criteria for potent inhibition and cell penetration. As a consequence, 10 new H. pylori antibiotic candidates are identified, all of which prevent H. pylori growth at concentrations 16-2000-fold lower than the five antibiotics, amoxicillin, metronidazole, levofloxacin, tetracyclin, and clarithromycin, commonly used to treat H. pylori infections. X-ray crystal structures of MTAN cocrystallized with several inhibitors show them to bind in the active site making interactions consistent with transition-state analogues.

Original languageEnglish (US)
Pages (from-to)14275-14280
Number of pages6
JournalJournal of the American Chemical Society
Volume137
Issue number45
DOIs
StatePublished - Nov 18 2015

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Wang, S., Cameron, S. A., Clinch, K., Evans, G. B., Wu, Z., Schramm, V. L., & Tyler, P. C. (2015). New Antibiotic Candidates against Helicobacter pylori. Journal of the American Chemical Society, 137(45), 14275-14280. https://doi.org/10.1021/jacs.5b06110