Molecular Basis for Enhanced Activity of Posaconazole against Absidia corymbifera and Rhizopus oryzae

Abstract

Posaconazole and itraconazole were more potent inhibitors of ergosterol synthesis, in both intact cells and cell extracts from Absidia corymbifera and Rhizopus oryzae, than voriconazole and fluconazole. Similarly, expression of CYP51 from R. oryzae in Saccharomyces cerevisiae significantly increased resistance to fluconazole and voriconazole but not to posaconazole and itraconazole.

Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

“…Posaconazole is frequently used off-label for the treatment of other documented mold infections, including invasive mucormycosis, when therapeutic options are limited. The enhanced potency of posaconazole against species of the order Mucorales relative to those of other triazoles may be explained, in part, by an increased affinity for fungal P450 demethylase (CYP51) and increased penetration or reduced efflux from the fungal cell membrane (1,2). Consequently, posaconazole MICs for Mucor, Rhizopus, Absidia, and Cunninghamella spp.…”

Three-dimensional models of 14α-sterol demethylase (Cyp51A) from Aspergillus lentulus and Aspergillus fumigatus: an insight into differences in voriconazole interaction

“…In agreement with this finding, Sheng et al [55] using the C. neoformans Cyp51 model showed that the higher affinity of voriconazole for the protein may be due to an extra hydrophobic interaction with the phenyl group of Y131. Moreover, substitutions in the regions surrounding residue F134 have also been related to voriconazole resistance shown by Absidia corymbifera and Rhizopus oryzae [62].…”

Posaconazole for the treatment of mucormycosis

“…These are summarised in Table 1 and show a range of minimum inhibitory concentrations (MICs) between ≤0.016 mg/L and > 16 mg/L [6][7][8][9][10][11].…”

“…Posaconazole (PCZ) is an orally administered, extended-spectrum triazole antifungal agent with activity against the Mucorales [5]. It is thought to be more active against the Mucorales than voriconazole, another broad-spectrum agent in the group, owing to a combination of increased affinity for the target site coupled with enhanced cellular penetration and/or reduced efflux [6]. This review describes the clinical and laboratory data supporting the use of PCZ against this rare group of pathogens.…”