Mode of Action and Resistance to Azole Antifungals Associated with the Formation of 14α-Methylergosta-8,24(28)-dien-3β,6α-diol

Kelly, Steven L.; Lamb, David C.; Corran, Andrew J.; Baldwin, Brian C.; Kelly, Diane

doi:10.1006/bbrc.1995.1272

Cited by 270 publications

(234 citation statements)

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“…5). However, cells can overcome the effect of such a block by a suppressor mutation in sterol C5,6 desaturation and can thus acquire azole resistance (69). In agreement with this observation, azole-resistant fungal isolates with nonfunctional ERG3 alleles have been described for C. albicans and Candida dubliniensis (70)(71)(72).…”

Section: Discussionmentioning

confidence: 54%

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Forastiero

Mesa-Arango

Alastruey‐Izquierdo

et al. 2013

Antimicrob Agents Chemother

104

100

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Section: Discussionmentioning

confidence: 54%

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Forastiero

Mesa-Arango

Alastruey‐Izquierdo

et al. 2013

Antimicrob Agents Chemother

104

100

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“…In the presence of fluconazole, the ERG11 gene product, lanosterol demethylase, is inhibited, leading to the accumulation of toxic sterol precursors and the production of alternate sterols, such as lanosterol, eburicol, obtusifoliol, 14␣-methyl fecosterol, and 14␣-methylergosta-8,24(28)-dien-3␤,6␣-diol (21). Integration of these sterols into the plasma membrane disrupts its integrity, resulting in its altered structure and function (12,43,44).…”

Section: G980ementioning

confidence: 99%

“…Disruption of ERG11 or pharmacologic inhibition of the enzyme it encodes leads to reduced ergosterol production and the accumulation of alternate sterols, including lanosterol, eburicol, obtusifoliol, 14␣-methyl fecosterol, and 14␣-methylergosta-8,24(28)-dien-3␤,6␣-diol (21). Biosynthesis of these alternate sterols does not require ERG11 but does require other genes in the ergosterol biosynthesis pathway, some of which appear to be regulated by Upc2.…”

mentioning

confidence: 99%

UPC2 Is Universally Essential for Azole Antifungal Resistance in Candida albicans

et al. 2014

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In Candida albicans, the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2-activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains. In addition to the reduced fluconazole MIC previously observed with UPC2 disruption, we observed a lower minimum fungicidal concentration (MFC) for a upc2⌬/⌬ mutant than for its azole-susceptible parent, SC5314. Moreover, the upc2⌬/⌬ mutant was unable to grow on a solid medium containing 10 g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed higher fungistatic activity against the upc2⌬/⌬ mutant than against SC5314. UPC2 disruption in strains carrying specific resistance mutations also resulted in reduced MICs and MFCs. UPC2 disruption in a highly azole resistant clinical isolate containing multiple resistance mechanisms likewise resulted in a reduced MIC and MFC. This mutant was unable to grow on a solid medium containing 10 g/ml fluconazole and exhibited increased susceptibility and a clear zone of inhibition by Etest. Time-kill analysis showed increased fungistatic activity against the upc2⌬/⌬ mutant in the resistant background. Microarray analysis showed attenuated induction by fluconazole of genes involved in sterol biosynthesis, iron transport, or iron homeostasis in the absence of UPC2. Taken together, these data demonstrate that the UPC2 transcriptional network is universally essential for azole resistance in C. albicans and represents an attractive target for enhancing azole antifungal activity.

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“…8). Although cholesterol available from the serum could provide a buffering capacity in membranes to counter the potentially toxic 14 ␣ -methyl sterol intermediates ( 46,47 ), cells died in LDM, nonetheless, when the media was supplemented with a combination of the two drugs ( Fig. 3G ).…”

Section: Effects Of Inhibitors and Rnai Treatment Of Tb Smt On Bsf Grmentioning

confidence: 99%

Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth

Haubrich¹,

Singha²,

Miller³

et al. 2015

Journal of Lipid Research

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Abbreviations: AZA, 25-azalanosterol; BSF, bloodstream form; DOX, doxycycline; ED, effective dose; FGM, full-growth medium; ITC, itraconazole; LDM, lipid-depleted medium; PCF, procyclic form; RRTc, relative retention time with cholesterol used as standard; SAM, S-adenosyl-lmethionine; SDM, sterol C14-demethylase; SMT, sterol C24-methyltransferase; Tb SDM, Trypanosoma brucei analyzed by RNAi silencing and inhibition of sterol C14-demethylase; Tb SMT, Trypanosoma brucei analyzed by RNAi silencing and inhibition of sterol C24-methyltransferase; TetR, tetracycline repressor .

show abstract

Mode of Action and Resistance to Azole Antifungals Associated with the Formation of 14α-Methylergosta-8,24(28)-dien-3β,6α-diol

Cited by 270 publications

References 0 publications

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

UPC2 Is Universally Essential for Azole Antifungal Resistance in Candida albicans

Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth

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