Anna Karawajczyk

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BACKGROUND Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection(More)
BACKGROUND Azoles play an important role in the management of Aspergillus diseases. Azole resistance is an emerging global problem in Aspergillus fumigatus, and may develop through patient therapy. In addition, an environmental route of resistance development has been suggested through exposure to 14α-demethylase inhibitors (DMIs). The main resistance(More)
Since 1998, the rapid emergence of multi-azole-resistance (MAR) was observed in Aspergillus fumigatus in the Netherlands. Two dominant mutations were found in the cyp51A gene, a 34bp tandem repeat (TR) in the promoter region combined with a leucine to histidine substitution at codon 98 (L98H). In this study, we show that molecular dynamics simulations(More)
Molecular studies have shown that the majority of azole resistance in Aspergillus fumigatus is associated with amino acid substitutions in the cyp51A gene. To obtain insight into azole resistance mutations, the cyp51A gene of 130 resistant and 76 susceptible A. fumigatus isolates was sequenced. Out of 130 azole-resistant isolates, 105 contained a tandem(More)
Based on studies with chimeras between (non-)gastric H,K-ATPase and Na,K-ATPase, a model for the ouabain binding site has recently been presented (Qiu et al. J.Biol.Chem. 280 (2005) 32349). In this model, hydrogen bonds between specific amino acid residues of Na,K-ATPase and hydroxyl groups of ouabain play a crucial role. In the present study, a series of(More)
The Aspergillus fumigatus cyp51A gene TR46/Y121F/T289A mutation is a new emerging resistance mechanism with high-level voriconazole (VOR) resistance, and elevated MICs to all other medical azoles. This is highly worrisome as VOR is the primary drug for the treatment of many aspergillus diseases. The 46 base pair tandem repeat (TR46) is positioned at the(More)
High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated,(More)
The European Lead Factory (ELF) is a public-private partnership (PPP) that provides researchers in Europe with a unique platform for translation of innovative biology and chemistry into high-quality starting points for drug discovery. It combines an exceptional collection of small molecules, high-throughput screening (HTS) infrastructure, and hit follow-up(More)
The introduction of silicon in biologically-relevant molecules represents an interesting medicinal chemistry tactic. Its use is mainly confined to the fine-tuning of specific molecular properties and organosilicon compounds are underrepresented in typical screening libraries. As part of the European Lead Factory efforts to generate novel, drug(More)