ArticleJournal of the American Chemical Society2015
New Antibiotic Candidates against Helicobacter pylori.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Beyond Urease: New Potential Enzymatic Targets inACS omega · 2026Review
- Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis.Biochemistry · 2023Article
- Antimicrobial activities of metabolites isolated from endophytic Aspergillus flavus of Sarcophyton ehrenbergi supported by in-silico study and NMR spectroscopy.Fungal biology and biotechnology · 2023Article
- Residence Times for Femtomolar and Picomolar Inhibitors of MTANs.Biochemistry · 2023Article
- MAT Gain of Activity Mutation inACS infectious diseases · 2023Article
- Inhibition of the futalosine pathway for menaquinone biosynthesis suppresses Chlamydia trachomatis infection.FEBS letters · 2021Article
- Aminofutalosine Deaminase in the Menaquinone Pathway ofBiochemistry · 2021Article
- Helicobacter pylori treatment in the post-antibiotics era-searching for new drug targets.Applied microbiology and biotechnology · 2020Review
- Transition State Analogues Enhanced by Fragment-Based Structural Analysis: Bacterial Methylthioadenosine Nucleosidases.Biochemistry · 2020Article
- Characterization of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidases from Borrelia burgdorferi: Antibiotic targets for Lyme disease.Biochimica et biophysica acta. General subjects · 2020Article
- Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase.Journal of medicinal chemistry · 2019Article
- Antibacterial Strategy againstACS medicinal chemistry letters · 2019Article
- Searching for potent and specific antibiotics against pathogenic Helicobacter and Campylobacter strains.Journal of industrial microbiology & biotechnology · 2019Review
- Enzymatic Transition States and Drug Design.Chemical reviews · 2018Review
- Transition-State Analogues of Campylobacter jejuni 5'-Methylthioadenosine Nucleosidase.ACS chemical biology · 2018Article
- Immucillins in Infectious Diseases.ACS infectious diseases · 2018Review
- Novel essential amino acid-sulfanilamide hybrid as safe anti-ulcerogenic agent with anti-Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2017Article
- Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase.ACS chemical biology · 2017Article
- Transition State Analogue Inhibitors of 5'-Deoxyadenosine/5'-Methylthioadenosine Nucleosidase from Mycobacterium tuberculosis.Biochemistry · 2017Article
- Efficient diastereoselective synthesis of a new class of azanucleosides: 2'-homoazanucleosides.Tetrahedron · 2017Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Helicobacter pylori is a Gram-negative bacterium that colonizes the gut of over 50% of the world's 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.