The title of the post is a copy and paste from the first two paragraphs of the linked academic press release here :
The amoeba Naegleria fowleri is commonly found in warm swimming pools, lakes and rivers. On rare occasions, the amoeba can infect a healthy person and cause severe primary amebic meningoencephalitis, a “brain-eating” disease that is almost always fatal. Other than trial-and-error with general antifungal medications, there are no treatments for the infection.
Researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego have now identified three new molecular drug targets in N. fowleri and a number of drugs that are able to inhibit the amoeba’s growth in a laboratory dish. Several of these drugs are already approved by the U.S. Food and Drug Administration for other uses, such as antifungal agents, the breast cancer drug tamoxifen and antidepressant Prozac.
Wenxu Zhou, Anjan Debnath, Gareth Jennings, Hye Jee Hahn, Boden H. Vanderloop, Minu Chaudhuri, W. David Nes, Larissa M. Podust.
Enzymatic chokepoints and synergistic drug targets in the sterol biosynthesis pathway of Naegleria fowleri.
PLOS Pathogens, 2018; 14 (9): e1007245
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.
Sterols are important constituents of cell membranes. In a unicellurar organism, such as the human pathogen N. fowleri, the cell membrane delineates the physical boundaries of the cell and mediates interactions of the organism with its environment. N. fowleri is a free-living amoeba that may infect the human brain causing a fulminant infection called primary amebic meningoencephalitis (PAM). PAM has resulted in death in >97% of reported cases. Understanding the molecular and cellular biology of N. fowleri will facilitate the rational development of new therapeutic interventions. Using inhibitors targeting different enzymatic steps in the sterol biosynthesis pathway, we mapped metabolic intermediates and delineated the biosynthetic routes contributing to N. fowleri sterol homeostasis. An array of sterol molecules suggests that two different sterol types, ergosterol-like and cholesterol-like sterols, co-exist and may be dynamically regulated in N. fowleri. Disruption of sterol biosynthesis by drug candidates was detrimental to N. fowleri. Drugs targeting three different enzymatic steps resulted in growth inhibition effect. This effect was amplified when drugs targeting different enzymes were combined. The observed synergistic effect of these drugs lowers the individual drug concentrations required for biological activity including delivering anti-PAM drugs across the blood-brain-barrier.