CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
In: PLoS neglected tropical diseases, vol 11, iss 12 PLoS Neglected Tropical Diseases, Jg. 11 (2017-12-28), Heft 12, p e0006104
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Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered “rare” (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug ‘repurposing’—a cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14-demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially ‘druggable’ target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.
Author summary The free-living amoeba, Naegleria fowleri, is commonly found in water sources including swimming pools having inadequate levels of chlorine, lakes, and rivers. N. fowleri can act as an opportunistic pathogen causing severe brain injury called Primary Amebic Meningoencephalitis (PAM), often in healthy children and young adults. With a fatality rate over 97%, N. fowleri is considered one of the most deadly human pathogens. Despite the fact that precious lives are lost annually, N. fowleri infection is rare and economic incentives to invest in development of anti-PAM drugs by the pharmaceutical industry are lacking. In the absence of economic inducements, drug ‘repurposing’ is a cost effective strategy for re-profiling known drugs for the treatment of neglected diseases. The similarity between pathogenic fungi and free-living amoebae in the sterol biosynthesis pathway encouraged us to assess anti-mycotic drugs, clinically-approved for treatment of a variety of fungal diseases, for anti-Naegleria activity. Carrying out biochemical studies and x-ray-crystallography of the target enzyme, we demonstrated that azole anti-fungal drugs, known as conazoles, disrupt sterol biosynthesis in amoebae by competing with the natural substrate for binding in the active site of the sterol 14-demethylase (CYP51). Disruption of sterol biosynthesis leads to a rapid death of pathogenic amoebae.
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CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
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Autor/in / Beteiligte Person: | Luth, Madeline R. ; Calvet, Claudia M. ; Jennings, Gareth K. ; Aksenov, Alexander A. ; Debnath, Anjan ; Podust, Larissa M. ; Zhou, Wenxu ; McKerrow, James H. ; Abagyan, Ruben ; W. David Nes ; Reynolds, Todd B |
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Zeitschrift: | PLoS neglected tropical diseases, vol 11, iss 12 PLoS Neglected Tropical Diseases, Jg. 11 (2017-12-28), Heft 12, p e0006104 |
Veröffentlichung: | eScholarship, University of California, 2017 |
Medientyp: | unknown |
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