Suche
Mein Konto
The discovery may lead to the development of new systems of antifungal drugs
Mycosis is an infectious disease caused by parasitic molds or yeasts and is treated with an antifungal, a subgroup of antibiotics. However, fungi - like humans - are eukaryotes, so developing new antifungals that are toxic to fungi while being safe for humans is a difficult problem that Associate Professor Yoshihiro Ojima and Professor Masayuki Azuma, from the Osaka Metropolitan University Graduate School of Engineering, are trying to solve. They focused on toyocamycin, an antibiotic known to work against the pathogenic yeast Candida albicans but not to kill baker's yeast (Saccharomyces cerevisiae). Candida albicans causes...
The discovery may lead to the development of new systems of antifungal drugs
Mycosis is an infectious disease caused by parasitic molds or yeasts and is treated with an antifungal, a subgroup of antibiotics. However, fungi - like humans - are eukaryotes, so developing new antifungals that are toxic to fungi while being safe for humans is a difficult problem that Associate Professor Yoshihiro Ojima and Professor Masayuki Azuma, from the Osaka Metropolitan University Graduate School of Engineering, are trying to solve. They focused on toyocamycin, an antibiotic known to work against the pathogenic yeast Candida albicans but not to kill baker's yeast (Saccharomyces cerevisiae). Candida albicans causes candidiasis; However, toyocamycin is also toxic to humans and is therefore not used to treat Candida albicans infections.
Antifungal agents effective against pathogenic eukaryotes are more difficult to develop than antimicrobials; There are only about 10 drugs available for treatment in four systems.”
Professor Masayuki Azuma, Osaka Metropolitan University Graduate School of Engineering
The researchers were intrigued because S. cerevisiae, unlike humans and C. albicans, does not have a gene for a concentrative nucleoside transporter (CNT). They suspected that the reason why toyocamycin is effective against C. albicans but not against S. cerevisiae is because it is transported into C. albicans by the CNT protein. So they tested toyocamycin on C. albicans, in which the CNT gene had been disrupted through genome editing.
Loss of the CNT gene rendered toyocamycin ineffective against C. albicans, suggesting that toyocamycin is internalized into cells through the CNT protein. They also found that S. cerevisiae became sensitive to toyocamycin when human CNT3 was introduced into cells through gene recombination.
The uptake of toyocamycin and its analogues by the C. albicans and human CNT3 proteins was tested by introducing the genes into S. cerevisiae. Tests with toyocamycin and analogues showed that their uptake varied depending on the structure and shape of the molecule.
“This discovery, learning how different CNT proteins deliver toyocamycin into cells, could lead to the development of new systems of antifungals with unprecedented modes of action,” said Professor Ojima.
By focusing on structural differences between analogues, new antifungals that are only effective against C. albicans and harmless to humans could be developed to treat candidiasis or other mycoses in the future.
Source:
Reference:
Ojima, Y., et al. (2022) Concentrative Nucleoside Transporter, CNT, results on the selective toxicity of toyocamycin against Candida albicans. Microbiological spectrum. doi.org/10.1128/spectrum.01138-22.
.