ArticlePLoS pathogens2018
Enzymatic chokepoints and synergistic drug targets in the sterol biosynthesis pathway of Naegleria fowleri.
Article in PLoS pathogens, 2018. 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.
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- Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads.Biomolecules · 2024Review
- Utilizing metagenomic next-generation sequencing and phylogenetic analysis to identify a rare pediatric case ofFrontiers in microbiology · 2024Article
- Miconazole-like Scaffold is a Promising Lead forJournal of medicinal chemistry · 2023Article
- The anti-amoebic potential of carboxamide derivatives containing sulfonyl or sulfamoyl moieties against brain-eating Naegleria fowleri.Parasitology research · 2023Article
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- A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling UsingPathogens (Basel, Switzerland) · 2022Article
- A Fluorometric Assay for theMicrobiology spectrum · 2022Article
- Relaxed Substrate Requirements of Sterol 14α-Demethylase fromJournal of medicinal chemistry · 2021Article
- Primary Amoebic Meningoencephalitis byBiomolecules · 2021Review
- Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads.Expert review of anti-infective therapy · 2021Article
- Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba.PloS one · 2021Article
- Phytosterol Profiles, Genomes and Enzymes - An Overview.Frontiers in plant science · 2021Review
- Domain-Swap Dimerization ofMolecular pharmacology · 2020Article
- HMG-CoA Reductase Inhibitors as Drug Leads againstACS chemical neuroscience · 2020Article
- In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor againstPathogens (Basel, Switzerland) · 2020Article
- In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole againstPathogens (Basel, Switzerland) · 2020Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Naegleria fowleri is a free-living amoeba that can also act as an opportunistic pathogen causing severe brain infection, primary amebic meningoencephalitis (PAM), in humans. The high mortality rate of PAM (exceeding 97%) is attributed to (i) delayed diagnosis, (ii) lack of safe and effective anti-N. fowleri drugs, and (iii) difficulty of delivering drugs to the brain. Our work addresses identification of new molecular targets that may link anti-Naegleria drug discovery to the existing pharmacopeia of brain-penetrant drugs. Using inhibitors with known mechanism of action as molecular probes, we mapped the sterol biosynthesis pathway of N. fowleri by GC-MS analysis of metabolites. Based on this analysis, we chemically validated two enzymes downstream to CYP51, sterol C24-methyltransferase (SMT, ERG6) and sterol Δ8-Δ7 -isomerase (ERG2), as potential therapeutic drug targets in N. fowleri. The sterol biosynthetic cascade in N. fowleri displayed a mixture of canonical features peculiar to different domains of life: lower eukaryotes, plants and vertebrates. In addition to the cycloartenol→ergosterol biosynthetic route, a route leading to de novo cholesterol biosynthesis emerged. Isotopic labeling of the de novo-synthesized sterols by feeding N. gruberi trophozoites on the U13C-glucose-containing growth medium identified an exogenous origin of cholesterol, while 7-dehydrocholesterol (7DHC) had enriched 13C-content, suggesting a dual origin of this metabolite both from de novo biosynthesis and metabolism of scavenged cholesterol. Sterol homeostasis in Naegleria may be orchestrated over the course of its life-cycle by a "switch" between ergosterol and cholesterol biosynthesis. By demonstrating the growth inhibition and synergistic effects of the sterol biosynthesis inhibitors, we validated new, potentially druggable, molecular targets in N. fowleri. The similarity of the Naegleria sterol Δ8-Δ7 -isomerase to the human non-opioid σ1 receptor, implicated in human CNS conditions such as addiction, amnesia, pain and depression, provides an incentive to assess structurally diverse small-molecule brain-penetrant drugs targeting the human receptor for anti-Naegleria activity.
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