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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.

Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase