A.A.Sagatova
et al.
(2016).
Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14α-demethylase.
Sci Rep,
6,
26213.
PubMed id: 27188873
DOI: 10.1038/srep26213
Emergence of fungal strains showing resistance to triazole drugs can make
treatment of fungal disease problematic. Triazole resistance can arise due to
single mutations in the drug target lanosterol 14α-demethylase (Erg11p/CYP51).
We have determined how commonly occurring single site mutations in pathogenic
fungi affect triazole binding using Saccharomyces cerevisiae Erg11p (ScErg11p)
as a target surrogate. The mutations Y140F/H were introduced into full-length
hexahistidine-tagged ScErg11p. Phenotypes and high-resolution X-ray crystal
structures were determined for the mutant enzymes complexed with short-tailed
(fluconazole and voriconazole) or long-tailed (itraconazole and posaconazole)
triazoles and wild type enzyme complexed with voriconazole. The mutations
disrupted a water-mediated hydrogen bond network involved in binding of
short-tailed triazoles, which contain a tertiary hydroxyl not present in
long-tailed triazoles. This appears to be the mechanism by which resistance to
these short chain azoles occurs. Understanding how these mutations affect drug
affinity will aid the design of azoles that overcome resistance.
Links
