NDLI: Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy

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Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy

Content Provider	Semantic Scholar
Author	McLellan, Catherine A. Vincent, Benjamin Matteson Solis, Norma V. Lancaster, Alexander K. Sullivan, Lucas B. Hartland, Cathy L. Youngsaye, Willmen Filler, Scott G. Whitesell, Luke Lindquist, Susan L.
Copyright Year	2018
Abstract	The development of effective antifungal therapeutics remains a formidable challenge because of the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability because of its differential utilization in fungi and its pivotal roles in fungal morphogenesis, virulence, and drug resistance already demonstrated by others. We now report mechanistic characterization of ML316, a thiohydantoin that kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1. Using genetic, biochemical, and metabolomic approaches, we established ML316 as the first Mir1 inhibitor. Inhibition of Mir1 by ML316 in respiring yeast diminished mitochondrial oxygen consumption, resulting in an unusual metabolic catastrophe marked by citrate accumulation and death. In a mouse model of azole-resistant oropharyngeal candidiasis, ML316 reduced fungal burden and enhanced azole activity. Targeting Mir1 could provide a new, much-needed therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infection.
Starting Page	135
Ending Page	141
Page Count	7
File Format	PDF HTM / HTML
PubMed reference number	29227471v1
Alternate Webpage(s)	https://doi.org/10.1038/nchembio.2534
DOI	10.1038/nchembio.2534
Journal	Nature chemical biology
Volume Number	14
Language	English
Access Restriction	Open
Subject Keyword	Antifungal Agents Azoles Candida albicans reaction wheal^1D post 50 ug Candida albicans ID:Diam:Pt:Skin:Qn Cessation of life FSD1 gene Genetics, Biochemical Metabolic Process, Cellular Metabolomics Mitochondrial Diseases Mitochondrial Inheritance Morphogenesis Mycoses Thiohydantoins inorganic phosphate negative regulation of reactive oxygen species biosynthetic process oropharyngeal candidiasis phosphate ion transport sodium citrate
Content Type	Text
Resource Type	Article

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