The current antifungal treatments aren’t effective against the fungi. The situation is getting more complicated because these organisms are developing resistance to antimicrobial treatments just as bacteria are. Researchers report in ACS Infectious Diseases that they have identified compounds that tackle these infections in a novel way -; by interfering with fungal enzymes that are required for the synthesis of fatty acids possibly opening the way to more effective treatments.
While superficial infections caused by Candida and other fungi can be uncomfortable and cause minor problems such as athlete’s feet and oral thrush and oral thrush, invasive infections can lead to deadly and debilitating diseases such as cryptococcal meningitis, or any hospital acquired infection. These conditions are becoming more frequent because of the growing use of invasive surgery and implanted catheters, and immunosuppressive therapies. Patients suffering from severe COVID-19 and HIV are more susceptible to fungal infections. Due to the increase in resistance to treatment, it is possible that they are harmful and may not always work. The most recent targets for these compounds are molecules necessary for making fungal cell walls. Glen. E. Palmer and colleagues began looking for potential treatments that could operate through a different mechanism and thereby be able to avoid the negative side effects of these drugs.
The researchers focused on fungal fatty acid (FA) synthase and desaturase enzymes, which are essential for the growth and virulence of human fungal pathogens. Because it is difficult to identify these enzymes, it has been difficult to create a rapid chemical test to determine inhibitors. So the team instead combined genetic engineering with a whole-cell test to identify thousands of small molecules. Although none of the tested compounds inhibited FA synthase activity in Candida albicans cell lines 16 inhibited FA desaturase activity. A central acyl hydrazide structure was identified as crucial to the function of many of these molecules, that were effective even against drug-resistant strains of several infectious species of fungi, but exhibiting little or no toxicity to mammalian cells. These compounds have a promising future for further development as antifungal agent.
DeJarnette, C., and others. (2021) Identification of inhibitors of Fungal Fatty Acid Biosynthesis. ACS Infectious Diseases. doi.org/10.1021/acsinfecdis.1c00404.
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