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Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase
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Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase
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Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase
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Journal Article
Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase
2017
Overview
Mucormycoses are emerging and potentially lethal infections. An increase of breakthrough infections has been found in cohorts receiving short-tailed azoles prophylaxis (e.g. voriconazole (VCZ)). Although VCZ is ineffective
in vitro
and
in vivo
, long-tailed triazoles such as posaconazole remain active against mucormycetes. Our goal was to validate the molecular mechanism of resistance to short-tailed triazoles in Mucorales. The paralogous cytochrome P450 genes (CYP51 F1 and CYP51 F5) of
Rhizopus arrhizus
,
Rhizopus microsporus
, and
Mucor circinelloides
were amplified and sequenced. Alignment of the protein sequences of the
R. arrhizus
,
R. microsporus
, and
M. circinelloides
CYP51 F1 and F5 with additional Mucorales species (n = 3) and other fungi (n = 16) confirmed the sequences to be lanosterol 14α-demethylases (LDMs). Sequence alignment identified a pan-Mucorales conservation of a phenylalanine129 substitution in all CYP51 F5s analyzed. A high resolution X-ray crystal structure of
Saccharomyces cerevisiae
LDM in complex with VCZ was used for generating a homology model of
R. arrhizus
CYP51 F5. Structural and functional knowledge of
S. cerevisiae
CYP51 shows that the F129 residue in Mucorales CYP51 F5 is responsible for intrinsic resistance of Mucorales against short-tailed triazoles, with a V to A substitution in Helix I also potentially playing a role.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/22
/ 45/23
/ 64
/ 82
/ 82/81
/ Amino Acid Substitution - genetics
/ Azoles
/ Drug Resistance, Fungal - drug effects
/ Fungi
/ Homology
/ Humanities and Social Sciences
/ Science
/ Sterol 14-Demethylase - chemistry
/ Sterol 14-Demethylase - genetics
/ Structural Homology, Protein
/ Structure-function relationships
/ Yeast
