New drug shows synergy with antifungal drugs to kill drug-resistant bacteria

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A study conducted at the University of São Paulo (USP) in Brazil found that the new drug brilacidin, which was being tested to treat conditions ranging from bacterial skin infections to COVID-19, was divided into two classes. was shown to be able to kill drug-resistant fungal strains when combined with An over-the-counter antifungal drug.

A potential application of this drug is patented and reported in the following paper (https://www.nature.com/articles/s41467-023-37573-y). Nature Communications. It was discovered by researchers at the Ribeirao Preto Faculty of Pharmacy (FCFRP-USP) supported by FAPESP (https://bv.fapesp.br/en/auxilios/109067).

The problem of drug resistance is a problem recognized by the World Health Organization (WHO), but the development of new drugs is costly and time-consuming. “For this reason, we set out to identify the antifungal activity of known chemical molecules that had not been studied for their effect on fungal growth inhibition. In this case, we investigated 1,400 compounds before arriving at brilacidin. I did,” said Taira Fernanda Doss. Reis (https://bv.fapesp.br/en/pesquisador/75349/thaila-fernanda-dos-reis) is the first author of the paper and a postdoctoral fellow at FCFRP-USP.

Using several different methods, the researchers found that combining brilacidin with one of two antifungal drugs (caspofungin or voriconazole) resulted in resistant strains of several fungal species that cause infections in humans. I concluded that I could kill. Aspergillus fumigatuscauses invasive pulmonary aspergillosis.

Aspergillosis is a common infection in the intensive care unit (ICU) with a mortality rate of 60% to 90%. It also affects people with compromised immune systems, such as those undergoing cancer treatment (read Click here for details: https://agencia.fapesp.br/39521 and https://agencia.fapesp.br/36064).

In addition to its combination with antifungal drugs for lung infections, brilacidin alone also blocked the growth of lung infections. A. fumigatus Fungal keratitis is a corneal infection that affects 1-2 million people worldwide annually, and is often caused by corneal abrasion caused by plant debris, especially in tropical countries with extensive agricultural activities. Wearing fungal-contaminated contact lenses is a major risk factor in the United States and other developed countries.

working mechanism

Drug resistance occurs when microorganisms (fungi, bacteria, or viruses) find ways to survive and continue to grow in the presence of drugs that inhibit their growth. Therefore, it is important to have multiple drugs with different mechanisms of action so that if a strain develops resistance, he can choose one drug over another.

However, there are nine classes of antibacterial agents, whereas only four classes of antifungal agents are commercially available. Caspofungin is one example. It has been available for some time with a mechanism of action that inhibits the synthesis of the fungal cell wall, an integrity-related structure that surrounds the plasma membrane.

It is not uncommon for fungi to activate their repair systems when in contact with a drug, avoid the effects of the drug, and survive in its presence. The study noted the potential benefits of combining caspofungin and brilacidin in terms of inactivating this repair system.

Caspofungin never dies A. Frumigatus However, it prevents its growth. This is often enough for the host’s immune system to control the infection, but not always. Therefore, it is important to identify agents that can act synergistically with caspofungin. One option is to combine caspofungin and brilacidin to develop a single drug that works together. “


Gustavo Henrique Goldman, last author of the paper, FCFRP-USP Professor

super fungi

Another advantage of brilacidin discovered by the researchers was that it works against a wide variety of fungi in combination with caspofungin or voriconazole. In animal models, the combination of caspofungin and brilacidin was also effective against other species. A. fumigatuslike that Candida albicans, white ears and Cryptococcus neoformans.

These and other species are known as hyperfungals because of their strong resistance to drugs and are responsible for severe nosocomial infections. Such symptoms have become more common in recent times as more people have been admitted to intensive care units (ICUs) during the COVID-19 pandemic (read Click here for details: https://agencia.fapesp.br/40165 and https://agencia.fapesp.br/36111).

Researchers found that the combination of brilacidin and voriconazole was effective against both diseases. A. fumigatus and mucocele species that cause severe facial deformity are found mainly in India and Pakistan.

Clinical trials are needed to confirm efficacy in humans. In partnership with Innovation Pharmaceuticals, Inc. (IPI), a US-based company that owns the brilacidin patent, the researchers are now licensing the drug, conducting clinical trials, and marketing one of the combinations We are looking for Brazilian companies that are interested in The ordeal was successful.

This research also includes another project supported by FAPESP (https://bv.fapesp.br/en/auxilios/95467/).

sauce:

Sao Paulo Research Foundation (FAPESP)

Reference magazines:

Dos Reis, TF, other. (2023) The host defense peptidomimetic brilacidin enhances the antifungal activity of caspofungin against human pathogenic fungi.. Nature Communications. doi.org/10.1038/s41467-023-37573-y.

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