What Happened
- Scientists at CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, led by Dr. Sriram Varahan, discovered that a metabolic link between glycolysis (sugar breakdown) and sulfur-containing amino acid production controls the ability of fungi to switch from harmless yeast forms to dangerous invasive filamentous forms.
- The study, published in eLife (February 6, 2026), showed that disrupting glycolysis in Candida albicans weakened the fungus, reduced its ability to evade immune cells (macrophages), and caused only mild infections in mouse models.
- When sulfur-containing amino acids (cysteine and methionine) were supplied externally to metabolically compromised fungi, they regained their ability to invade, confirming the specific metabolic dependency.
- The findings suggest a novel antifungal strategy: instead of killing fungi directly (which promotes drug resistance), future therapies could target fungal metabolism to prevent the morphological switch that makes fungi pathogenic.
Static Topic Bridges
Candida albicans and Fungal Morphological Switching
Candida albicans is the most common human fungal pathogen, responsible for infections ranging from superficial mucosal candidiasis (oral thrush, vaginal infections) to life-threatening invasive candidiasis in immunocompromised patients. Its pathogenicity is closely linked to its ability to switch between a harmless oval yeast form and an invasive filamentous (hyphal) form, a process called morphological switching or dimorphism.
- The yeast-to-hyphae transition is considered the most critical virulence trait of C. albicans; mutants locked in either form show diminished virulence.
- Environmental triggers for the switch include temperature (37 degrees Celsius), serum, neutral pH, CO2, and N-acetylglucosamine.
- Hyphal cells are invasive and essential for tissue penetration, organ colonization, and escaping macrophage killing.
- Key molecular regulators include the cAMP-PKA signalling pathway, transcription factors Efg1, Cph1, and Ume6, and repressors Nrg1 and Tup1.
- The WHO published its first-ever Fungal Priority Pathogens List in 2022, classifying C. albicans in the "critical priority" group.
Connection to this news: The CCMB study reveals a previously uncharacterized metabolic layer controlling this morphological switch, specifically showing that glycolysis-generated sulfur amino acids are essential for filament formation, adding a metabolic dimension to the established genetic regulatory framework.
Glycolysis and Central Carbon Metabolism
Glycolysis is the fundamental metabolic pathway by which cells break down glucose into pyruvate, generating ATP and NADH. It occurs in the cytoplasm and is the first step of both aerobic and anaerobic respiration. In fungi, glycolytic flux is tightly linked to virulence and adaptation to different host environments.
- The pathway involves 10 enzymatic steps, converting one glucose molecule into two pyruvate molecules, with a net gain of 2 ATP and 2 NADH.
- Phosphofructokinase-1 (Pfk1) is a key rate-limiting enzyme of glycolysis; the CCMB study found that disrupting Pfk1 impaired fungal morphogenesis.
- Glycolytic inhibitors tested in the study include 2-Deoxy-D-Glucose (2DG) and sodium citrate.
- The study revealed a conserved dependency between central carbon metabolism and de novo biosynthesis of sulfur-containing amino acids across both Saccharomyces cerevisiae (baker's yeast) and Candida albicans.
Connection to this news: The discovery that glycolytic flux directly controls sulfur amino acid production, which in turn controls the yeast-to-hyphae switch, establishes glycolysis as a druggable target for antifungal therapy, potentially offering a novel approach that avoids the resistance problems of conventional antifungals.
Antifungal Resistance: A Growing Global Concern
Antifungal resistance is an escalating public health crisis, with the WHO warning that invasive fungal infections cause more than 1.5 million deaths annually worldwide. The existing antifungal drug arsenal is extremely limited compared to antibacterials, with only four major classes available: azoles, echinocandins, polyenes, and the newer triterpenoid class (ibrexafungerp, approved 2021).
- Azole-resistant C. albicans and Candida auris (an emerging multidrug-resistant species first identified in Japan in 2009) pose particular clinical challenges.
- Candida auris has caused outbreaks in hospitals across India, the US, and other countries; some strains are resistant to all three major antifungal classes.
- The mucormycosis ("black fungus") outbreak during India's COVID-19 second wave (2021) highlighted the devastating impact of fungal infections in immunocompromised patients.
- India's ICMR has established antifungal susceptibility testing networks to track resistance patterns.
Connection to this news: The CCMB discovery of a metabolic "Achilles' heel" in pathogenic fungi opens a fundamentally different therapeutic strategy: disarming fungi by disrupting their metabolism rather than trying to kill them, which could be harder for fungi to develop resistance against.
Key Facts & Data
- Institution: CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad.
- Lead researcher: Dr. Sriram Varahan; co-authors: Dhrumi Shah, Nikita Rewatkar, Adishree M, Siddhi Gupta, Sudharsan Mathivathanan, Sayantani Biswas.
- Published in eLife, February 6, 2026 (DOI: 10.7554/eLife.109075).
- Organisms studied: Candida albicans (pathogenic) and Saccharomyces cerevisiae (model yeast).
- Key enzyme: Phosphofructokinase-1 (Pfk1), a glycolytic enzyme whose disruption impaired morphogenesis.
- Glycolytic inhibitors used: 2-Deoxy-D-Glucose (2DG) and sodium citrate.
- Sulfur amino acids (cysteine, methionine) rescued invasive capacity when supplied externally.
- Methods: genetic manipulation, pharmacological inhibition, transcriptomic analysis, and in vivo murine infection models.
- WHO Fungal Priority Pathogens List (2022): C. albicans classified as "critical priority."
- Invasive fungal infections cause over 1.5 million deaths annually worldwide (WHO estimate).