3D metal complexes could be the answer to overcoming fungal drug-resistance

In this previous study, Blaskovich and colleagues demonstrated that metal compounds, such as the platinum-containing anticancer drug cisplatin, showed antibacterial capabilities. They then conducted the first large-scale screening to look into their antifungal potential.

In a statement to the university, Dr. Blaskovich reveals, "we found 21 percent of the metal compounds screened showed antifungal activity – compared to only one percent of the 300,000 non-metal compounds screened previously."

The scientist also explained that those metal compounds with the highest antifungal activity showed low toxicity in initial tests. Therefore, it undermines the commonly held notion that metal-containing compounds are inherently (more) toxic.

Fungal infections cause 1.5 million deaths a year- new treatments desperately needed

"Fungal infections cause an estimated 1.5 million deaths a year and are especially dangerous for people who are immunocompromised, such as chemotherapy and transplant patients," explains Blaskovich.

The scientist highlights that while bacteria are becoming resistant to antibiotics, the bacteria that cause meningitis and skin, lungs, and bloodstream infections are also evolving resistance to the known therapies.

Blaskovich clarifies that "there are only ten antifungal drugs in various phases of clinical development at the moment, and not all of them will pass trials to make it to patients, so we urgently need more options."

The untapped potential of 3D metal complexes to overcome resistance

The community for Open Antimicrobial Drug Discovery (CO-ADD), which gathered the substances and carried out the preliminary screening for this investigation, was founded by Dr. Blaskovich.

The researcher describes that the three-dimensional structure of metal complexes enables them to function differently than current antifungal medications and potentially overcome resistance.

"CO-ADD offers free testing of new compounds from research groups around the world, as well as a searchable database to accelerate the discovery of antibiotics and antifungal drugs," states Blaskovich.

The professor announced that the team would like more scientists to submit their metal complexes for antimicrobial testing. This way, new antifungal medications can be manufactured more quickly to avoid a crisis of resistance.

Abstract:

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivoG. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.