Investigating the potential of mitochondrial inhibition as an antifungal target in Cryptococcus neoformans

The opportunistic pathogen Cryptococcus neoformans is the major causal agent of cryptococcosis and cryptococcal meningitis in HIV patients worldwide, and increasing evidence of antifungal resistance demands that new therapeutic targets are investigated. Here, we review the roles of mitochondria, respiration and metabolism in C. neoformans pathogenesis and discuss the role of the Alternative Oxidase enzyme (Aox). Our data suggests that C. neoformans was sensitive to mitochondrial disruption and that resistance of this organelle to stress is partly linked to Ypk1, a kinase involved in lipid biosynthesis pathways. We propose that Aox1 plays an important role in the decision to enter quiescence when mitochondria are placed under respiratory stress, potentially as part of a metabolic checkpoint. Investigations into efficacy of the antimicrobial agent sodium nitrite, and the effects of novel, putative fungal-specific inhibitors ALTOX094 and ALTOX102 are discussed. We found that these compounds had potential as dual inhibitors of Aox and cytochrome bc1, which reduced C. neoformans growth and viability. However, these drugs had variable effects on respiration, indicative of different mechanisms of mitochondrial disruption. We suggest that tackling C. neoformans infection through mitochondrial inhibition presents a viable future direction for research. Further investigations to extend our findings around the role of mitochondria and metabolism in the control of quiescence may reveal new approaches to tackle the pathogenicity of C. neoformans.