Creation of metal-based antibiotics to fight harmful fungal infections

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An international group of researchers from University of Bern and the University of Queensland in Australia have shown that chemical compounds including specialty metals are very effective in fighting harmful fungal infections. These discoveries could be applied to create breakthrough drugs effective against resistant fungi and bacteria.

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Every year, more than a billion people are infected with a fungal infection. Although these infections are mostly harmless, more than 1.5 million patients die from infection each year. As fungal strains are increasingly detected as being resistant to one or more of the available drugs, the creation of new drugs has all but come to a standstill in recent years. Currently, only a dozen clinical trials are underway with new active agents for the treatment of fungal infections.

Compared to over a thousand cancer drugs currently being tested in human subjects, this is an exceptionally small number.

Dr. Angelo Frei, lead study author, Department of Chemistry, Biochemistry and Pharmacy, University of Bern

The results of the study have been published in the journal JACS Au.

Boosting antibiotic research with crowdsourcing

To inspire the creation of antifungal and antibacterial agents, scientists at the University of Queensland in Australia created the Community for Open Antimicrobial Drug Discovery (CO-ADD). The company’s aspiring goal is to discover new antimicrobial active agents by giving chemists around the world the opportunity to test any chemical compound against fungi and bacteria for free.

As Frei explains, the preliminary focus of CO-ADD surrounded “organic” molecules, which primarily include the elements carbon, oxygen, hydrogen, and nitrogen and do not include any metals.

However, Frei, who is trying to create new metal-based antibiotics with his study group at the University of Bern, found that more than 1,000 of the more than 300,000 compounds tested by CO-ADD carry metals.

For most people, when used in conjunction with the word “people”, the word metal triggers a feeling of unease. The opinion that metals are fundamentally harmful to us is widely held. However, this is only partially true. The decisive factor is the metal used and in what form.

Dr. Angelo Frei, lead study author, Department of Chemistry, Biochemistry and Pharmacy, University of Bern

Dr. Frei is responsible for all metal compounds in the CO-ADD database.

Low toxicity demonstrated

In their new research, the team focused on metal compounds that showed activity against fungal infections. During the study, 21 highly active metal compounds were tested against several resistant fungal strains. These carried the metals nickel, cobalt, molybdenum, rhodium, silver, palladium, europium, platinum, iridium and gold.

Many metal compounds demonstrated good activity against all fungal strains and were up to 30,000 times more active against fungi than against human cells.

Dr. Angelo Frei, lead study author, Department of Chemistry, Biochemistry and Pharmacy, University of Bern

The highly active compounds were then tested in a model organism, wax moth larvae. The scientists noticed that only one of the eleven metal compounds tested showed signs of toxicity, while the others were well tolerated by the larvae. In the next step, a few metal compounds were tested in an infection model, and one compound was successful in reducing fungal infection in larvae.

Considerable potential for wide application

Metallic compounds have been used in the field of medicine: cisplatin, for example, which contains platinum, is one of the most widely used anti-cancer drugs. Despite this, there is a long process before new antimicrobial drugs containing metals are authorized.

We hope that our work will enhance the reputation of metals in medical applications and motivate other research groups to further explore this vast but relatively unexplored area. If we harness the full potential of the periodic table, we may be able to prevent a future where we don’t have effective antibiotics and active agents to prevent and treat fungal infections.

Dr. Angelo Frei, lead study author, Department of Chemistry, Biochemistry and Pharmacy, University of Bern

The research has received support from the Swiss National Science Foundation, the University of Queensland and the Wellcome Trust, among others.

Journal reference:

Frei, A. et al. (2022) Metal complexes as antifungals? From a participatory compound library to the first in vivo experiments. JACS Au. doi.org/10.1021/jacsau.2c00308.

Source: https://www.unibe.ch

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