Antifungal resistance, explained
How fungi survive the drugs meant to kill them.
The most common antifungal drugs, the azoles, all work the same way: they disable one enzyme the fungus needs to live. Resistance comes down to three ways a fungus gets around that. Scroll through each one.
One enzyme, one drug, one weak point.
Fungi need a molecule called ergosterol to build their cell membranes, and they rely on an enzyme called Cyp51 (encoded by the ERG11 gene) to make it. Azole drugs fit into Cyp51 and place a nitrogen atom against the iron at its core, which shuts the enzyme down. With no working enzyme there is no ergosterol, and with no ergosterol there is no membrane. Each mechanism below breaks a different link in that chain.
Three escape routes
Resistance is not one trick but several.
A resistant fungus rarely invents anything new. It reuses machinery it already has, in three main ways: change the shape of the target, pump the drug back out, or make more of the target than the drug can cover.
Mechanism 1 · target-site mutation
1. Change the target's shape
Start with the drug working normally. Its nitrogen reaches the iron, the enzyme is frozen, and the fungus cannot make ergosterol.
Mechanism 2 · efflux pumps
2. Pump the drug out
The drug has to build up inside the cell to work. Fungal membranes carry pumps: proteins that move unwanted molecules back outside.
Mechanism 3 · target overexpression
3. Make more of the target
A dose contains only so much drug. Here it blocks the few enzyme copies the fungus normally makes.
Why it's spreading
Resistance is moving out of the clinic and onto the farm.
Candida auris
A yeast first identified in 2009. It spreads between patients in hospitals, survives on surfaces for weeks, and is often resistant to several antifungal classes at once. The WHO ranks it a critical-priority pathogen.
Azoles in agriculture
The same azole chemistry is sprayed on crops at large scale. Molds like Aspergillus fumigatus encounter these fungicides in the soil and can evolve resistance there, before a patient ever takes a related drug.
An empty pipeline
We have only a handful of antifungal drug classes, and few new ones are close. Every mechanism a fungus acquires narrows an already thin set of options.
This is the gap we work on.
Telling a molecule that genuinely binds the enzyme from one that only appears to is a problem of geometry, the same geometry resistance exploits. Measuring it carefully is what our first project set out to prove.