H Munayyer

Posaconazole Is a Potent Inhibitor of Sterol 14α-Demethylation in Yeasts and Molds

ABSTRACT Posaconazole (POS; SCH 56592) is a novel triazole that is active against a wide variety of fungi, including fluconazole-resistant Candida albicans isolates and fungi that are inherently less susceptible to approved azoles, such as Candida glabrata. In this study, we compared the effects of POS, itraconazole (ITZ), fluconazole (FLZ), and voriconazole (VOR) on sterol biosynthesis in strains of C. albicans (both azole-sensitive and azole-resistant strains), C. glabrata, Aspergillus fumigatus, and Aspergillus flavus. Following exposure to azoles, nonsaponifiable sterols were extracted and resolved by liquid chromatography and sterol identity was confirmed by mass spectroscopy. Ergosterol was the major sterol in all but one of the strains; C. glabrata strain C110 synthesized an unusual sterol in place of ergosterol. Exposure to POS led to a decrease in the total sterol content of all the strains tested. The decrease was accompanied by the accumulation of 14α-methylated sterols, supporting the contention that POS inhibits the cytochrome P450 14α-demethylase enzyme. The degree of sterol inhibition was dependent on both dose and the susceptibility of the strain tested. POS retained activity against C. albicans isolates with mutated forms of the 14α-demethylase that rendered these strains resistant to FLZ, ITZ, and VOR. In addition, POS was a more potent inhibitor of sterol synthesis in A. fumigatus and A. flavus than either ITZ or VOR.

Correlation between aminoglycoside resistance profiles and DNA hybridization of clinical isolates.

DNA hybridization data and aminoglycoside resistance profiles (AGRPs) were determined for 4,088 clinical isolates from three studies (United States, Belgium, and Argentina). The correlation between susceptibility profiles and hybridization results was determined with nine DNA probes. For each of the seven aminoglycoside resistance profiles which we were able to test, the data suggested at least two distinct genes could encode enzymes which lead to identical resistance profiles. Furthermore, the DNA hybridization data showed that individual strains carried up to six unique aminoglycoside resistance genes. DNA hybridization revealed interesting differences in the frequencies of these genes by organism and by country.

The human interferon-albumin interaction: The influence of albumin conformation

Abstract When human interferon is chromatographed on bovine serum albumin immobilized via a molecular arm to agarose, there is a selective, transient retention of the interferon. When albumin is defatted prior to immobilization, its interaction with interferon becomes stronger, suggesting that hydrophobic binding is a major force in complex formation. The strength of the interferon-albumin interaction correlates with the extent of deformation of the albumin ligand. Human interferons, induced either by rI n ·rC n or Newcastle disease virus (NDV), are retained to the same extent, thus suggesting the existence of common structural features involved in their interactions with immobilized albumin.