Hira, D. | bioRxiv Science

bioRxiv2026

Identification of a pharmacokinetic interaction between teicoplanin and sulfo-butyl ether-β-cyclodextrin, an excipient in the intravenous posaconazole formulation

Patients undergoing hematopoietic stem cell transplantation (HSCT) often receive multiple antibiotics and antifungals concurrently, making it crucial to understand their potential pharmacokinetic interactions of these agents. We report here an interaction between the glycopeptide antibiotic teicoplanin (TEIC) and sulfo-butyl ether-{beta}-cyclodextrin (SBECD), a solubilizing excipient in the intravenous formulation of posaconazole (PSCZ). We performed a single-center retrospective analysis of patients who underwent HSCT and received oral and intravenous PSCZ during TEIC therapy. The associations between PSCZ administration and TEIC concentration-to-dose (C/D) ratios were evaluated using linear mixed-effects models. We also examined the effects of intravenous PSCZ and SBECD on TEIC pharmacokinetics in rats by assessing the area under the concentration-time curve (AUC) and urinary excretion of total TEIC and its components. In addition, molecular docking and in vitro protein-binding assays were conducted to investigate the interaction between TEIC and SBECD. In patients who underwent HSCT, TEIC C/D ratio was significantly lower following intravenous PSCZ administration than without administration. In contrast, the effect of oral PSCZ administration relative to non-administration was not statistically significant. In rats, intravenous PSCZ and SBECD decreased the AUC of TEIC and increased urinary excretion, particularly in the A2 group. Docking simulations indicated that the hydrophobic side chain of TEIC A2-2 fit within the SBECD cavity, and in vitro assays confirmed SBECD concentration-dependent increases in TEIC unbound fractions. The co-administration of intravenous PSCZ containing SBECD may reduce TEIC protein binding, thereby enhancing renal excretion.

pharmacology and toxicology↗

bioRxiv2023

Discovery of N-Glycan Outer Chain like α-(1->6)-linked Mannan Structures in Aspergillus fumigatus Mycelium

The cellular surface of the pathogenic filamentous fungus Aspergillus fumigatus is enveloped in a mannose layer, featuring well-established fungal-type galactomannan and O-mannose type galactomannan. This study reports the discovery of cell wall component in the mycelium that resemble N-glycan outer chains found in yeast. The glycosyltransferases involved in their biosynthesis in A. fumigatus were identified, with a focus on two key -(1[->]2)-mannosyltransferases, Mnn2 and Mnn5, and two crucial -(1[->]6)-mannosyltransferases, Mnn9 and Van1. In vitro examination revealed the roles of Mnn2 and Mnn5 in transferring -(1[->]2)-mannosyl residues. 1H-NMR analysis of cell wall extracts from the {Delta}mnn2{Delta}mnn5 strain indicated the existence of an -(1[->]6)-linked mannan backbone in the mycelium, with Mnn2 and Mnn5 adding -(1[->]2)-mannosyl residues to this backbone. The -(1[->]6)-linked mannan-derived chemical shift was absent in strains where mnn9 or van1 was disrupted in the parental {Delta}mnn2{Delta}mnn5 strain. Co-expressed Mnn9 and Van1 functioned as -(1[->]6)-linked mannan polymerases in heterodimers, suggesting their crucial role in biosynthesizing the -(1[->]6)-linked mannan backbone. Disruptions in these mannosyltransferases did not affect fungal-type galactomannan biosynthesis. The study provides insights into the complexity of fungal cell wall architecture and a comprehensive understanding of mannan biosynthesis in A. fumigatus, including the presence of outer chain like mannan structures and their potential role in cell wall integrity. ImportanceThis study unravels the complexities of mannan biosynthesis in A. fumigatus, a key area for antifungal drug discovery. It reveals the presence of outer chain like mannan structures, offering fresh insights into the fungal cell walls design. Key enzymes Mnn2, Mnn5, Mnn9, and Van1 are instrumental in this process, with Mnn2 and Mnn5 adding specific mannose residues and Mnn9 and Van1 assembling the outer chain like structures. While fungal-type galactomannanspresence in the cell wall is known, the existence of outer chain like mannan adds a new dimension to our understanding. This intricate web of mannan biosynthesis opens avenues for further exploration and enhances our understanding of fungal cell wall dynamics, paving the way for targeted drug development.

microbiology↗