Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy

Abstract

The development of effective antifungal therapeutics remains a formidable challenge due to the close evolutionary relationship between humans and fungi. Mitochondrial function may present an exploitable vulnerability due to 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 which kills drug-resistant Candida species at nanomolar concentrations through fungal-selective inhibition of the mitochondrial phosphate carrier Mir1. We established ML316 as the first Mir1 inhibitor using genetic, biochemical, and metabolomic approaches. 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.

Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation

“…In addition to their conventional roles in cellular energetics, metabolism, and cell signaling, mitochondria in C. albicans are involved in the actions of efflux pumps, oxidative stress responses, iron homeostasis, hyphal growth, and the synthesis of cell membrane components, namely ergosterol and the cell wall 46 – 48 . Targeting mitochondria is considered an effective approach to combat Candida infections, especially those arising from resistant strains 49 . The ability of TPP + to target the mitochondria supports the promising applications of this moiety in overcoming resistant fungal pathogens.…”

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…The molecule used against them is mannose-binding lectin (MBL), a protein that is synthesized in the liver and involved in complement cascade activation. Investigations of its function have found MBL-induced agglutination in the yeast Recombinant heat shock proteins: r-hsp90-CA [9,11] Laminarin: CRM197 [12] Replicative aging [23][24][25] Respiratory pathways: Mir1 [26] Sphingolipid metabolism: BHBM, D13 [27] Micafungin activated metacaspase complexes [28] Tricyclic antidepressants [16] Genetically engineered organisms: Lactobacillus casei containing the Eno1p antigen [29] phase to treat both C. glabrata and C. albicans. This was achieved through binding to the mannoproteins covering the fungal cell surface, inducing complement activation [15•].…”

Isomannide monoundecenoate‐based 1,2,3‐triazoles: Design, synthesis, and in vitro bioactive evaluation

“…Candidiasis, aspergillosis, and cryptococcosis are most frequently occurred fungal pathogenic infections due to high mortality and morbidity. [63,64] Among them, notably Candida albicans is a most widely causing fungal pathogenic infections in humans. [65] Further, immunologically deficient patients and patients who are undergoing treatment for cancer chemotherapy, children and HIV-AIDS infected individuals are greater prone to Candidiasis.…”