iKIX1

Research use only, not for human use.

iKIX1 is an Pdr1-dependent gene activation. It re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection.

iKIX1 is an Pdr1-dependent gene activation. It re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection.

iKIX1 (10-20 μg/ml)?inhibits cell growth in a concentration-dependent manner in the presence of 5 μM ketoconazole (KET) in HepG2 cells.FP titration curve showing the interaction of?CgGal11A KIX domain with?CgPdr1 AD30 fitted to a Kd?of 319.7 nM.?iKIX1?competes out?CgPdr1 AD30 with an IC50 of 190.2 μM . In vitro?binding studies, iKIX1 reveals that the Kd of the?CgPdr1 activation domain (AD) for the?CgGal11A KIX domain is 0.32 μM and the apparent Ki for?iKIX1?is 18 μM.iKIX1 (0-50 μM) inhibits Ketoconazole (KET)-induced upregulation of luciferase activity in a dose-responsive manner in a?Sc pdr1Δpdr3Δ?strain containing plasmid-borne?CgPDR1?and 3XPDRE-luciferase.A chromatin immunoprecipitation (ChIP) assay is used to examine Gal11/Med15 recruitment to Pdr1-regulated target genes in?S. cerevisiae. Ketoconazole induces Gal11/Med15 rapidly recruited to the promoters of the Pdr1 target genes?PDR5?and?SNQ2. iKIX1 abrogates Ketoconazole-induced recruitment of Gal11/Med15 and strongly inhibits azole-induced transcription of?ScPdr1 target genes. iKIX1?(20 μM) has an effect on the transcription of?C. glabrata?Pdr1-regulated genes involved in drug efflux and MDR (CgCDR1, CgCDR2?and?CgYOR1).?iKIX1?alone does not significantly affect Pdr1-target gene induction. But pre-treatment with iKIX1?reduces ketoconazole-induced CgPdr1 up-regulation in a durable and concentration-dependent manner. In RNA sequencing (RNA-Seq) assay of a?C. glabrata SFY114 (PDR1?wild-type) strain.?Azole up-regulates Pdr1-dependent genes in both yeasts, such as the drug efflux pumps?ScPDR5?and?CgCDR1i. KIX1?combines azole strongly blunts expression of many azole-activated and Pdr1-dependent genes in both?S.cerevisiae?and?C. glabrata, but iKIX1?alone affects very different sets of genes in?S.cerevisiae?and?C. glabrata. And then iKIX1?does not significantly alter the expression of?PDR1?or?GAL11/MED15 affects very different sets of genes in?S.cerevisiae and?C. glabrata. iKIX1?(0-150 μM) restores the efficacy of azoles towards?CgPDR1?gain-of-function mutants. It restores azole-sensitivity to?PDR1?gain-of-function mutant strains in a concentration-dependent manner.

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Microbiology/Virology

Antifungal

Antifungal

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656222-54-7

303.16

C10H8Cl2N4OS

>98% (HPLC)

In Vitro:?DMSO : 83.33 mg/mL (274.86 mM)

Clc1ccc(NC(=S)NNC(=O)CC#N)cc1Cl

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(-20℃)

With Ice Pack

≥ 2 years