- In pre-clinical studies, Brilacidin shown to synergize with marketed antifungals against pathogenic species of aspergillosis, candidiasis, cryptococcosis and mucormycosis, and further exhibited potent stand-alone efficacy against Cryptococcus neoformans
- These data suggest Brilacidin has potential as a novel antifungal agent
Fernanda dos Reis T ,Alves de Castro P , Bastos R, Pinzan CF, Souza PFN, Ackloo S, Hossain MA, Drewry D, Alkhazraji S, Ibrahim A, Hyunil J, DeGrado WF. “A Host Defense Peptide Mimetic, Brilacidin, Potentiates Caspofungin Antifungal Activity Against Human Pathogenic Fungi.”
bioRxiv 2022.09.28.509882; doi.org/10.1101/2022.09.28.509882
Summary of Brilacidin Antifungal Research Findings
Following an in vitro drug screening of 1,402 compounds, Brilacidin showed promising antifungal activity and was subsequently selected for additional pre-clinical evaluation, including in combination with caspofungin (CAS), voriconazole (VOR), and posaconazole (POSA), all current antifungal treatments.
In cell culture, in Aspergillus fumigatus (A. fumigatus), Brilacidin converted CAS from a fungistatic into a fungicidal drug, enabling it to overcome both drug resistance and biofilm formation. Brilacidin exerted, to a lesser degree, synergistic effects with VOR in A. fumigatus. Further in vitro testing showed Brilacidin synergized with CAS in C. albicans, C. auris and C. neoformans. In an A. fumigatus immunosuppressed mouse model in invasive pulmonary aspergillosis, Brilacidin plus CAS cleared infection in the lungs by almost 95 percent, compared to ~50 percent when each compound was administered individually. Brilacidin also showed in vitro an additive inhibitory effect when combined with POSA in several species of Mucorales, the main etiological agents of mucormycosis, commonly referred to as black fungus. Mortality rates can be as high as 90 percent in this fungal disease.
Interestingly, Brilacidin showed potent in vitro stand-alone efficacy (MIC=2.5µM) in C. neoformans, a major driver of illness in people living with HIV/AIDS. C. neoformans, for which few effective treatments are available, causes an estimated 220,000 cases of cryptococcal meningitis worldwide each year and is associated with an 80 percent mortality rate.
A proposed antifungal mechanism of action of Brilacidin involves membrane depolarization by impacting calcineurin and cell wall integrity, as informed by protein kinase inhibitory experiments and genetic screenings of protein phosphatase null mutants.
“It is a remarkable feature of Brilacidin that it can potentiate multiple antifungals, in different pathogenic fungi, including hard-to-treat species. New antifungal combination strategies are urgently needed due to a scarcity of novel agents, alongside emerging resistance in the clinical setting,” commented
About Antifungal Diseases 1, 2, 3
There are up to 5 million fungal species populating the earth, of which approximately 100,000 species have been identified. About 300 fungal species cause disease in humans. Overall, Candida, Cryptococcus and Aspergillus represent the main causative organisms of invasive fungal infections. There is a large unmet medical need for developing novel antifungal agents, particularly given the emergence of resistance in the clinical setting. The utility of current antifungal treatments is limited due to toxicity, fungistatic and not fungicidal properties, as well as drug interaction concerns. In
1 Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy
2 Global Caspofungin Market Research Report 2022 (Status and Outlook)
3 Antifungal Drugs Market Size to be worth
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