Novel mitochondrial-targeted alkyl chains act as fungal specific inhibitors of C. neoformans
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Updated: May 27, 2025
Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
Elizabeth S M Edrich1, Luke Young2, John Spencer2
1Kent Fungal Group, School of Biosciences, University of Kent, Kent, United Kingdom.
Abstract:
Cryptococcus neoformans is the causal agent of cryptococcal meningitis in immunocompromised patients and increasing instances of anti-fungal resistance have led to investigations into new alternative antifungal targets. For example, C. neoformans possesses an Alternative Oxidase enzyme (Aox) that has been implicated in stress resistance and virulence that may represent a viable antifungal target. Here we test the efficacy of mitochondrially-targeted Colletochlorin B, which has been shown to inhibit the Aox of Candida albicans in vitro. Two derivatives of Colletochlorin B, which we modified to improve delivery to mitochondria, were identified as putative fungal-specific inhibitors. ALTOX094 and ALTOX102 were able to inhibit Aox and cytochrome bc 1 in vitro and demonstrated strong inhibitory effects against C. neoformans growth and viability. Further analysis suggested that the antifungal properties of ALTOX094 and ALTOX102 were attributable to different modes of action and forms of cell death, governed largely by the alkyl chain length used to tether Colletochlorin B to the mitochondria targeting triphenylphosphine (TPP) moiety. Our findings add to the growing evidence that functionalized mitochondria targeted alkyl chains may developed further as an effective class of antifungal and are effective against C. neoformans.
Insights
New antifungal compounds targeting the Alternative Oxidase (Aox) enzyme show promise against Cryptococcus neoformans. Modified Colletochlorin B derivatives effectively inhibited fungal growth, offering potential new treatments for cryptococcal meningitis.
Area of Science:
- Biochemistry
- Mycology
- Drug Discovery
Background:
- Cryptococcus neoformans causes meningitis in immunocompromised individuals.
- Increasing antifungal resistance necessitates novel therapeutic targets.
- The Alternative Oxidase (Aox) enzyme in C. neoformans is implicated in virulence and stress resistance.
Purpose of the Study:
- To evaluate the antifungal efficacy of mitochondrially-targeted Colletochlorin B derivatives against C. neoformans.
- To investigate the mechanism of action of these novel compounds.
- To explore the potential of Aox as a viable antifungal target.
Main Methods:
- Synthesis of two Colletochlorin B derivatives (ALTOX094, ALTOX102) with enhanced mitochondrial delivery.
- In vitro inhibition assays targeting Aox and cytochrome bc1.
- Assessment of fungal growth inhibition and viability assays against C. neoformans.
- Analysis of structure-activity relationships based on alkyl chain length.
Main Results:
- ALTOX094 and ALTOX102 demonstrated potent inhibition of Aox and cytochrome bc1 in vitro.
- Both compounds exhibited strong inhibitory effects on C. neoformans growth and viability.
- Antifungal activity was linked to different modes of action and cell death pathways, influenced by the mitochondria-targeting moiety.
Conclusions:
- Mitochondria-targeted Colletochlorin B derivatives are effective against C. neoformans.
- Functionalized mitochondria-targeted compounds represent a promising class of antifungals.
- Further development of these compounds could lead to new treatments for fungal infections.
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