amphotericin-b and pyrimidine

Candida infections frequently involve drug-resistant biofilm growth on device surfaces. Glucan synthase gene FKS1 has been linked to triazole resistance in Candida biofilms. We tested the impact of FKS1 modulation on susceptibility to additional antifungal classes. Reduction of FKS1 expression rendered biofilms more susceptible to amphotericin B, anidulafungin, and flucytosine. Increased resistance to anidulafungin and amphotericin B was observed for biofilms overexpressing FKS1. These findings suggest that Candida biofilm glucan sequestration is a multidrug resistance mechanism.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Biofilms; Candida albicans; Drug Resistance, Fungal; Echinocandins; Flucytosine; Fungal Proteins; Glucans; Glucosyltransferases; Humans; Microbial Sensitivity Tests; Polyenes; Pyrimidines

Indazole regioisomers such as 3-amino-4-(trifluoromethyl)-6-phenyl-1H-indazole-7-carbonitrile 1 and 3-amino-6-(trifluoromethyl)-4-phenyl-1H-indazole-7-carbonitrile 2 were independently reacted with formaldehyde followed by unsymmetrical, symmetrical and cyclic electron rich olefins in presence of GdCl(3) as catalyst and obtained pyrimidine fused indazole derivatives 3 and 4, respectively. The reaction is found to be concerted and an exclusive product is formed. Representative examples of compounds 3 and 4 were screened against Gram-positive, Gram-negative bacteria and fungal species such as yeast and filamentous fungi in vitro. Compound 3f showed significant activity against all species of Gram-positive and Gram-negative bacteria, whereas compounds 3h and 4a showed the least activity with reference to penicillin as well as streptomycin. Similarly compound 3c showed promising activity against yeast and filamentous fungi whereas compound 3f is inactive at the maximum concentration of 150 microg/mL.

Topics: Anti-Bacterial Agents; Antifungal Agents; Catalysis; Gadolinium; Indazoles; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microbial Sensitivity Tests; Pyrimidines

Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the beta-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida albicans; Caspofungin; Echinocandins; Flucytosine; Fungal Proteins; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Genome, Fungal; Humans; Ketoconazole; Lipopeptides; Microbial Sensitivity Tests; Oligonucleotide Array Sequence Analysis; Peptides, Cyclic; Polyenes; Pyrimidines