Why scientists are rethinking the chemical ‘arms race’ against fungi, Pg II

Key Highlights:

• Multidrug-resistant fungal infections, particularly from Candida auris, are rapidly emerging, posing a significant threat in ICU facilities with a 30-40% mortality rate.
• Global warming is identified as a key factor, applying selective pressure that favors heat-tolerant fungi capable of surviving in the human body, a concept known as the fungal infection – mammalian selection hypothesis.
• Research on Indian clinical isolates of Candida auris revealed widespread resistance to common antifungals like azoles (over 90%) and polyenes (30%), with echinocandins showing more efficacy.
• Genetic mechanisms of resistance include duplication of the Erg11 gene (leading to increased ergosterol production) and mutations in the Fks1 gene, which confer resistance to azoles and echinocandins, respectively.
• Scientists are advocating for more nuanced susceptibility tests and a shift from an "arms race" approach to targeting less critical fungal pathways or using combination therapies.

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Detailed Insights:

• Dermatophytosis, caused by dermatophytes, represents common skin fungal infections, but systemic infections like those by Candida auris are far more severe.
• Candida auris was first reported in Japan in 2009 and has since become a global menace, highlighting the recent increase in fungal pathogenicity.
• The Postgraduate Institute of Medical Education and Research (PGIMER) in Chandigarh has maintained a repository of 15,000 fungal isolates for 25 years, aiding research and identification.
• Current clinical susceptibility tests for antifungals like caspofungin may be insufficient, as Candida auris can resist concentrations higher than standard testing limits.
• The Eagle effect describes the paradoxical growth of fungi, where high concentrations of certain antifungals like caspofungin can activate compensatory pathways, such as increased chitin production, allowing survival.
• Future strategies involve combination therapies to overcome cellular compensatory pathways and developing antifungals that target less critical molecular pathways to reduce evolutionary pressure.

Scientific/Technical Concepts Involved:

• Dermatophytosis: Common fungal infections affecting skin, hair, and nails, caused by dermatophytes.
• Candida auris: An emerging, multidrug-resistant yeast pathogen known for causing severe, often untreatable, infections in healthcare settings.
• Fungal infection – mammalian selection hypothesis: Theory suggesting global warming selects for fungi that can tolerate higher temperatures, enabling them to infect mammals.
• Antifungals: Drugs used to treat fungal infections, categorized into classes like azoles, polyenes, and echinocandins, each targeting different fungal components.
• Ergosterol: A sterol found in the fungal cell membrane, analogous to cholesterol in animal cells, and a primary target for many antifungal drugs.
• Chitin: A structural polysaccharide that is a major component of the fungal cell wall, providing rigidity and protection.
• Eagle effect: A phenomenon where microorganisms exhibit paradoxical survival or growth at very high concentrations of an antimicrobial agent.