Published Feb 09, 2026 | 7:00 AM ⚊ Updated Feb 09, 2026 | 7:00 AM
Representational image. Credit: iStock
Synopsis: Scientists at Hyderabad’s CSIR-CCMB have discovered how fungi transform from harmless yeast into invasive filaments. The team found that rapid sugar breakdown fuels sulfur amino acid production, triggering shape-shifting and virulence. Blocking glycolysis weakened Candida infections in mice, but supplying sulfur compounds restored pathogenicity, revealing a metabolic pathway distinct from humans and a potential antifungal drug target.
You carry fungi inside you right now. They sit quietly in your gut, on your skin, in the warm corners of your body. Most of the time, they do nothing. Then, something shifts. The fungi sense it. Within hours, they transform. What was round becomes long. What was harmless becomes invasive. What floated through your bloodstream now pierces into your cells.
For years, doctors watched this happen without knowing why. They knew which genes turned on. They knew which signals fired. But they missed something hiding in plain sight: the fungi were following their hunger.
Scientists at the CSIR Centre for Cellular and Molecular Biology (CCMB) in Hyderabad have now traced the trigger. When fungi break down sugar faster, they produce sulfur compounds that flip a switch. The switch tells them to change shape. The new shape lets them invade.
Dr Sriram Varahan runs the laboratory where this discovery emerged. His team was not looking for genes this time. They were watching metabolism, the process that turns food into energy and building blocks.
“By looking at fungi through a metabolic lens, we uncovered what can be described as a previously hidden biological short circuit,” he says. “We discovered a crucial connection between the process by which cells break down sugar to generate energy, called glycolysis, and the production of specific sulfur-containing amino acids.”
Picture a fungus as it enters your body. It arrives as a yeast cell, round and small, about five microns across. That’s roughly the width of a red blood cell. It drifts through tissues, searching.
Then it finds a spot. Nutrients drop. Temperature changes. Other microbes press in. The fungus responds. It begins to stretch. Within hours, it extends into a filament 20 to 100 microns long. The filament drives forward like a root through soil.
Your immune cells struggle to clear these filaments. Medicines struggle too. The shape itself becomes a shield.
Scientists have known for decades which genetic switches control this transformation. Pathways like cAMP-PKA were thought to run the show. But Varahan’s team found something operating underneath.
They slowed down glycolysis, the process cells use to split sugar molecules and extract energy. When they did this in laboratory dishes, the fungi stayed round. They could not shift into filaments. They stayed harmless.
Then the researchers added sulfur compounds from outside. The fungi transformed immediately. The filaments grew. The invasion began again.
“This dramatic rescue demonstrated that these nutrients act like an essential on/off switch,” the researchers wrote in their study. “Without them, morphogenesis stalls. With them, the invasive transformation can restart.”
The team worked with two fungi. One was baker’s yeast, the organism humans have used for bread and beer for thousands of years. The other was Candida albicans, a pathogen that kills thousands of people each year through bloodstream infections.
Both fungi showed the same pattern. When glycolysis ran fast, genes for making cysteine and methionine switched on. These sulfur-containing amino acids then drove the shape change.
When glycolysis slowed, those genes shut down. The link held whether the team used chemicals to block sugar breakdown or deleted genes that encode enzymes in the pathway.
The team deleted a gene called PFK1, which makes an enzyme that sits early in glycolysis. The researchers found that the strain “became metabolically crippled,” according to their findings. It could not shift shape easily. It struggled to survive when immune cells called macrophages tried to eat it.
Then they tested the crippled fungus in mice. “This altered strain caused much milder disease compared to normal fungal strains,” the team reported. The infections stayed mild.
But when the researchers fed the mice N-acetyl cysteine, a sulfur compound, the fungus regained its power. Virulence returned. The infections worsened.
For years, scientists knew that glucose activates a receptor called Gpr1 on the fungal cell surface. This triggers production of a molecule called cAMP, which then activates an enzyme called protein kinase A.
“This glucose-dependent cAMP-PKA pathway has been shown to be essential for pseudohyphal differentiation under nitrogen-limiting conditions,” previous studies established.
The Hyderabad team tested this. They added cAMP directly to fungi with blocked glycolysis. It did nothing. The fungi stayed round.
They tried it with genetic mutants missing glycolysis enzymes. Again, cAMP failed to restore shape-shifting.
But when they tested a mutant lacking GPA2, a gene in the cAMP pathway itself, cAMP worked perfectly. It rescued that defect.
“These findings indicate that glycolysis controls pseudohyphal differentiation through a cAMP-PKA independent mechanism, likely via parallel metabolic regulation,” the authors concluded.
This meant glycolysis was working through a separate route. It was not just feeding the cAMP-PKA pathway. It was running a parallel system that nobody had mapped before.
The team dug into gene expression data. They compared fungi grown with and without glycolysis inhibitors. Hundreds of genes changed. But one pattern jumped out.
“We observed a striking and unexpected downregulation of multiple genes specifically involved in the biosynthesis and transport of sulfur-containing amino acids, cysteine and methionine,” the researchers reported. This happened at both early and late stages of pseudohyphal development.
Genes for making and transporting sulfur amino acids dropped sharply when glycolysis slowed. This included genes encoding Met4, the master regulator of sulfur metabolism, and Met32, its partner protein.
The team deleted MET32 in yeast. The mutant could still make cysteine and methionine because another gene, MET31, provides backup. But it could not shift shape well under nitrogen limitation, the condition that normally triggers the transformation.
Adding cysteine or methionine rescued the defect completely. This confirmed that sulfur metabolism sat downstream of glycolysis in controlling shape change.
The researchers traced the connection further. They found that a protein called Met30 acts as a switch. It controls Met4 activity. When glycolysis runs fast, Met30 allows Met4 to turn on sulfur metabolism genes. When glycolysis slows, something changes in Met30, and the pathway shuts down.
The team suspects this happens through a chemical modification of Met30, similar to what occurs when fungi encounter cadmium stress. But they have not yet identified the exact signal.
Everything the team learned in baker’s yeast applied to Candida albicans. “Our findings provide compelling evidence for a conserved metabolic network that intricately links central carbon metabolism, particularly glycolysis, sulfur amino acid biosynthesis, and fungal morphogenesis in both Saccharomyces cerevisiae and Candida albicans,” the authors stated.
When they blocked glycolysis in this human pathogen, it could not form hyphae, the invasive filaments it uses to penetrate tissues and evade immune cells.
Expression of sulfur metabolism genes dropped. Virulence genes stayed quiet. The fungus became less dangerous.
They tested it in macrophages, the immune cells that try to eat and destroy invading fungi. Normal Candida survives inside these cells. The glycolysis-impaired strain died.
They tested it in mice. Normal Candida causes systemic infections that spread through organs. The impaired strain caused mild, localised disease.
Then they gave the mice N-acetyl cysteine in their drinking water. The fungus roared back to life. “Supplying sulfur compounds to the host reversed this loss of virulence,” the researchers found, “underscoring how tightly fungal pathogenicity is wired to metabolism.” It formed hyphae. It spread through tissues. It killed mice at rates approaching those of normal strains.
The sulfur supply had restored the pathogen’s power.
Fungal infections kill more than 1.5 million people worldwide each year. That number rises as more people undergo chemotherapy, organ transplants, and other treatments that suppress immunity. Climate change is pushing fungi into new regions and helping them adapt to warmer temperatures, including the human body.
At the same time, the fungi are developing resistance to the few drugs available. There are only three major classes of antifungal medicines, compared to dozens of antibiotic classes. Many antifungals damage human cells along with fungal cells because the two cell types share so much biology.
Resistance is spreading. Some Candida strains now resist all available drugs. Doctors face infections they cannot treat.
This is where metabolism becomes important. The glycolysis-sulfur link that Varahan’s team identified exists in fungi but not in humans. Human cells make cysteine and methionine through different pathways. This creates a window for selective targeting.
“Since these pathways are fundamental for fungal growth and shape-shifting, they may represent an Achilles’ heel that is harder for fungi to escape through resistance,” Varahan says.
The team proposes that drugs targeting fungal metabolism might work differently from current antifungals.
“By disrupting the coupling between glycolysis and sulfur metabolism, future treatments could potentially blunt fungal virulence without killing the organism outright,” the researchers suggest. This strategy may slow drug resistance.
Instead of trying to kill the fungus, which drives resistance, such drugs could prevent the fungus from transforming into its invasive form. It would remain present but harmless, unable to cause disease.
(Edited by Amit Vasudev)
