Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy.

Nat Chem Biol
Authors
Keywords
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.

Year of Publication
2018
Journal
Nat Chem Biol
Volume
14
Issue
2
Pages
135-141
Date Published
2018 02
ISSN
1552-4469
DOI
10.1038/nchembio.2534
PubMed ID
29227471
PubMed Central ID
PMC5771894
Links
Grant list
R01 AI120958 / AI / NIAID NIH HHS / United States
R01 DE026600 / DE / NIDCR NIH HHS / United States
R03 MH086456 / MH / NIMH NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States