Finding fresh antifungals by pairing old drugs

As the world gets to grips with the ongoing COVID-19 pandemic, another public health crisis is looming. Fungi and bacteria are becoming resistant to antimicrobials at an alarming rate; infectious diseases could kill more people than cancer by 2050 if new strategies to quell microbes are not forthcoming, according to the World Health Organization. Now, scientists have found a fresh way to kill fungi or block their growth by combining drugs that are not currently used to treat fungal infections (ACS Infect. Dis. 2020, DOI: 10.1021/acsinfecdis.0c00405).

Researchers have previously improved the efficacy of existing antifungals by combining them with other drugs, but the scientists behind this latest study wanted to see if they could find a totally new way to kill fungi. They tested drug combinations against Candida albicans, the cause of oral thrush, as well as vaginal and other yeast infections. The scientists began with three drugs—paromomycin, an antibiotic; primaquine, an antimalarial; and ibuprofen, an anti-inflammatory—and then paired each with 1,280 other already approved drugs, yielding 3,840 different combinations. The researchers added the drug pairs to liquid cultures of C. albicans and measured how much of the fungi was either growth-limited or killed.

None of the drugs tested cure fungal infections by themselves, but 17 pairs worked synergistically to limit the growth of C. albicans. The three most effective pairs were paromomycin and β-escin, a horse chestnut extract sometimes used to treat swelling; primaquine and celecoxib, an anti-inflammatory; and ibuprofen and pentamidine, used to kill parasites.

“Considering we started with a fairly random approach, we’re pleased with that. To be honest, even one would have been good,” says Simon V. Avery, a microbiologist at the University of Nottingham who led the study. “It shows the potential of this method. If you tried more drugs, we think you might find other promising combinations.”

“They’re looking at pre-licensed compounds, and they’re all used every day, so we already have good toxicity data on them,” says Susu M. Zughaier, a microbiologist at Qatar University who was not involved with the study but is also looking for new antimicrobial compounds. “This could shorten the road to get these combinations into a clinical setting.”

She is, however, slightly concerned at the prospect of giving ibuprofen to patients with suppressed immune systems who are more likely to have infections, because the drug has a mild immunosuppressive effect. “We really need to see this replicated in vivo and beyond the lab with further testing and verification to be sure of safety.”

Although the specific antifungal combinations highlighted in the study warrant further examination, Avery hopes the study also has wider relevance as a proof of concept. “The same approach could be used against bacteria and other types of fungi,” he says.

Zughaier agrees. “The implication of this work goes beyond just C. albicans,” she says. “It’s pretty interesting.”