Researchers discover way to combat superfungi – 07/06/2023 – Health

A study conducted at USP reveals that brilacidin, a new drug tested for illnesses ranging from bacterial skin infections to Covid-19, can kill resistant strains of fungi when combined with two classes of antifungals available on the market.

The new potential application of the medicine, now patented and described in the journal Nature Communications, was discovered by researchers from the Faculty of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP), in the interior of São Paulo, supported by FAPESP.

The problem of drug resistance is a challenge recognized by the WHO (World Health Organization), but the process of developing a new drug is very expensive and time-consuming.

“For this reason, we sought to identify the antifungal activity of chemical molecules that were already known, but which until then had not been studied in terms of their effects on controlling fungal growth. In this case, we started by exploring 1,400 chemical compounds until we arrived at this one”, says Thaila Fernanda dos Reis, postdoctoral fellow at FCFRP-USP and first author of the article.

Thanks to the use of different methods, the researchers concluded that the combination of brilacidin with two different antifungal drugs (caspofungin or voriconazole) has the ability to kill resistant strains of several species of fungus that cause infections in humans, such as Aspergillus fumigatus, the causative agent of invasive pulmonary aspergillosis.

Aspergillosis is a common infection in patients admitted to intensive care units (ICUs), which can lead to death in between 60% and 90% of individuals. It also affects patients with a certain degree of immune impairment, such as those undergoing cancer treatments.

In addition to combinations with antifungals for lung infections, brilacidin alone blocked the growth of the A. fumigatus and disease development in an animal model of keratitis, an infection that affects the cornea.

The eye disease affects 1 to 2 million people a year worldwide, especially in tropical countries with great agricultural activity. In the United States and other developed countries, the use of contact lenses contaminated with mold is the main risk factor.

Mechanism of action

Drug resistance occurs when the microorganism (fungus, bacteria or virus) finds a way to survive and continue to multiply even in the presence of the drug that should stop its growth.

Therefore, it is important to have drug options that act in different ways on the pathogen, in order to eradicate the infection even when the strain is resistant to some drug. However, while there are nine classes of antibacterials, there are only four classes of antifungals commercially available.

Caspofungin, for example, is an antifungal that has been available on the market for a long time. Its mechanism of action consists of inhibiting the synthesis of the cell wall, a structure that surrounds the plasma membrane and maintains the integrity of the fungal cell.

When in contact with the drug, however, not infrequently, the fungus activates a repair system, which bypasses the action of the drug and allows it to survive in its presence. Hence the potential of the combination of caspofungin and brilacidin. In tests, the presence of the new molecule disabled the repair system triggered by caspofungin.

“Caspofungin does not kill the fungus A. fumigatus, but hinders its multiplication. This is often enough for the host’s immune system to control the infection, but not always. That is why it is important to identify drugs capable of acting in synergy with One of the options would be to create a single drug that combined caspofungin and brilacidin simultaneously, so that they could act together”, summarizes Gustavo Henrique Goldman, a professor at FCFRP-USP who coordinated the study.

Superfungi

Another advantage of brilacidin is that the combination with caspofungin or voriconazole had action against different species of fungus.

In tests with animal models, in addition to A. fumigatus, the combination of brilacidin with caspofungin was effective in inhibiting other fungal species such as Candida albicans, Candida auris and Cryptococcus neoformans.

Called “superfungi” because of their high drug resistance, some of these strains have been blamed for serious nosocomial infections. Recently, they have become more common due to the large number of hospitalizations in ICUs due to the COVID-19 pandemic.

The synergistic action of brilacidin with voriconazole, in turn, was effective both against A. fumigatus and against Mucorales, a fungus that occurs mainly in India and Pakistan and causes serious deformations of the face.

For the effects to be proven in humans, however, clinical trials are needed. Together with the company that owns the brilacidin patent, the North American Innovation Pharmaceuticals Incorporated, the researchers are now looking for a Brazilian company that can license the medicine in the country and carry out the clinical tests, necessary to prove the effects in humans and, in case of successfully make the drug available on the market.