Why Antifungal Drug Development Remains So Challenging According to John Rex, MD

Antimicrobial resistance is often discussed through the lens of bacteria, yet fungal pathogens present a distinct and increasingly urgent challenge. According to John Rex, MD, chief medical officer at F2G Ltd, in his interview with Infection Control Today^®, the biological realities of fungi make antifungal drug development uniquely difficult.

“Finding antifungal drugs is hard because we’re so closely related to the fungi. Eukaryotes are eukaryotes. We have most of our biology in common and so finding a target that is unique to fungi, not present in humans, so you could selectively hit just the fungus and not human beings, is biologically hard to find.”

Unlike bacteria, which possess multiple structures distinct from human cells, fungi share much of the same cellular machinery. “There are several systems in bacteria that are different from those in human beings. It’s been relatively easier to find nonhuman targets in bacteria than in fungi.”

One of the few shared therapeutic targets is the cell wall. “Human beings don’t have cell walls. Targets in the cell wall have been a good place to go for both antifungals and antibacterials.” However, beyond that, Rex notes, “the list gets pretty short after that.”

Why Invasive Fungal Infections Are So Dangerous

Rex emphasizes that the difficulty of treating invasive fungal infections is not only pharmacological but also patient vulnerability. Rex said, “Probably the most substantial thing about fungi that’s special is that most of the time meaningful fungal infections occur in people who are relatively immunocompromised.”

Fungi are ubiquitous. “You’re constantly surrounded by fungi. You’re breathing them right now.” Yet in healthy individuals, the immune system provides strong defense. “Our immune systems are quite good at keeping off fungi. When a fungal infection gets going, something substantial has gone wrong.”

He explains that fungi are biologically adapted to degrade tissue. “Biologically, what fungi do for a living is degrade dead tissue. When they get going in you, most fungal infections involve you becoming meaningfully more vulnerable in some way.”

Treatment is further complicated by the nature of antifungal drugs themselves. “The antifungal drugs, as a group, tend to inhibit the fungus rather than killing it. They tend to be static rather than -cidal.”

Limited Treatment Classes

For invasive fungal infections such as Candida and Aspergillus, options remain narrow. “There are only a few classes of licensed antifungal agents. The 3 big ones are the azoles, the echinocandins, and the amphotericin variations.”

Within each class, resistance patterns are often shared. “If a fungus is resistant to the azoles, it’ll be resistant to all of them. If 1 echinocandin doesn’t work, the other 2 won’t work either.”

This lack of diversification in mechanisms narrows therapeutic flexibility in resistant infections.

The Role of Combination Therapy

Combination therapy, commonly used in tuberculosis and HIV, plays a more limited role in fungal disease. Rex outlines 3 theoretical benefits of combination therapy: “Combinations as synergy, combinations as overlap, and combinations as mutual protection.”

Synergy means “A with B is better than either A or B.” Overlap provides coverage when susceptibility is uncertain. Mutual protection prevents resistance by attacking with multiple agents simultaneously.

“In fungi, it tends to be more about overlap,” he says. “It’s really hard to demonstrate synergy in a way that’s meaningful.” Unlike tuberculosis, where resistance emerges rapidly, “the rate of development of resistance to any one of the 3 major classes is pretty low.”

A Thin Pipeline

The antifungal pipeline is alarmingly small.

“Relative to pipelines for new therapies for cancer, for which there must be thousands, antibacterials we’re talking double-digit numbers in clinical development, and antifungals we’re talking single-digit numbers,” Rex said.

Several barriers slow progress. “Finding a new antifungal is hard. You go for a long time before you find an interesting start point.” Clinical trials are equally challenging. “The fungal infections are relatively uncommon, and they occur in people who are already very, very sick.”

Phase 3 trials can span years. “Three, 4, or 5 years would not be an uncommon duration at all for a phase 3 study of a new antifungal agent.”

Can AI Accelerate Discovery?

Artificial intelligence has generated excitement in drug discovery, but Rex urges caution. “It’s really easy to kill bacteria and fungi. Steam, fire, bleach. They work great. They’re just not drugs.”

A viable drug must survive the bloodstream, avoid toxicity, reach the infection site, and maintain activity. “Those are very, very special characteristics,” Rex said.

While artificial intelligence may identify antimicrobial activity, “what now needs to be incorporated is the AI knowing how to be trained to look for safety and drug-like characteristics.”

He remains cautiously optimistic. “I’m not ready for them to give up. I want them to keep going, because that’d be pretty cool.”

Antimicrobials as Fire Extinguishers

For infection preventionists, Rex frames antimicrobials through a powerful analogy. “Antibiotics are the fire extinguishers of medicine.” He asks, “Have you used a fire extinguisher today?” Probably not. Yet they must be available. “Infections go so fast, and if you don’t have a fire extinguisher in hand right away, you die.”

The challenge is economic. “The only way we currently pay for any drug is that I put it into a human being, and you pay me for it.”

But antimicrobials have value even when unused. He said, “They have value also in being handy and being available.”

Without reform, the model is fragile. Rex sighed, “We’ve had antibacterial companies bring drugs to market, get them approved, and then go out of business because there was not enough revenue to sustain the molecule in the market.”

Meanwhile, resistance is inevitable. Rex said, “There’s no amount of magic that will keep resistance from occurring. Resistance will continue to develop. Anything you invent is ultimately going to wear out.”

As fungal threats grow and the pipeline remains thin, prevention, stewardship, and sustained innovation are inseparable components of a single fire-protection strategy.