Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function

Zhu, Ping; Yue, Chaoping; Zeng, Xiaofeng; Chen, Xiulai

doi:10.3390/antiox11101855

Cited by 8 publications

(8 citation statements)

References 49 publications

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“…The antifungal drug flucytosine activates Pdr1 and induces CDR1 and fluconazole resistance in C. glabrata probably by interfering with mitochondrial function ( 50 ). The antimalarial drugs artemisinin and artesunate activated Pdr1 in C. glabrata ( 51 ) and S. cerevisiae ( 52 ) but also interfered with mitochondrial activities. Secondarily, the artemisinin-related molecules appeared to inhibit Cdr1 activity, and therefore, antagonism of fluconazole efficacy was not observed ( 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Redefining pleiotropic drug resistance in a pathogenic yeast: Pdr1 functions as a sensor of cellular stresses in Candida glabrata

Gale

Pavesic

Nickels

et al. 2023

mSphere

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Candida glabrata is a prominent opportunistic fungal pathogen of humans. The increasing incidence of C. glabrata infections is attributed to both innate and acquired resistance to antifungals. Previous studies suggest the transcription factor Pdr1 and several target genes encoding ABC transporters are critical elements of pleiotropic defense against azoles and other antifungals. This study utilizes Hermes transposon insertion profiling to investigate Pdr1-independent and Pdr1-dependent mechanisms that alter susceptibility to the frontline antifungal fluconazole. Several new genes were found to alter fluconazole susceptibility independent of Pdr1 ( CYB5 , SSK1 , SSK2 , HOG1 , TRP1 ). A bZIP transcription repressor of mitochondrial function ( CIN5 ) positively regulated Pdr1 while hundreds of genes encoding mitochondrial proteins were confirmed as negative regulators of Pdr1. The antibiotic oligomycin activated Pdr1 and antagonized fluconazole efficacy likely by interfering with mitochondrial processes in C. glabrata . Unexpectedly, disruption of many 60S ribosomal proteins also activated Pdr1, thus mimicking the effects of the mRNA translation inhibitors. Cycloheximide failed to fully activate Pdr1 in a cycloheximide-resistant Rpl28-Q38E mutant. Similarly, fluconazole failed to fully activate Pdr1 in a strain expressing a low-affinity variant of Erg11. Fluconazole activated Pdr1 with very slow kinetics that correlated with the delayed onset of cellular stress. These findings are inconsistent with the idea that Pdr1 directly senses xenobiotics and support an alternative hypothesis where Pdr1 senses cellular stresses that arise only after engagement of xenobiotics with their targets. IMPORTANCE Candida glabrata is an opportunistic pathogenic yeast that causes discomfort and death. Its incidence has been increasing because of natural defenses to our common antifungal medications. This study explores the entire genome for impacts on resistance to fluconazole. We find several new and unexpected genes can impact susceptibility to fluconazole. Several antibiotics can also alter the efficacy of fluconazole. Most importantly, we find that Pdr1—a key determinant of fluconazole resistance—is not regulated directly through binding of fluconazole and instead is regulated indirectly by sensing the cellular stresses caused by fluconazole blockage of sterol biosynthesis. This new understanding of drug resistance mechanisms could improve the outcomes of current antifungals and accelerate the development of novel therapeutics.

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Section: Discussionmentioning

confidence: 99%

Redefining pleiotropic drug resistance in a pathogenic yeast: Pdr1 functions as a sensor of cellular stresses in Candida glabrata

Gale

Pavesic

Nickels

et al. 2023

mSphere

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“…AlphaFold predicts at least one deep pocket in the core domain of Pdr1 that could potentially bind small metabolites (50). The antimalarial drugs artemisinin and artesunate activated Pdr1 in C. glabrata (51) and S. cerevisiae (52) but also interfered with mitochondrial activities. Secondarily, the artemisinin-related molecules appeared to inhibit Cdr1 activity and therefore antagonism of fluconazole efficacy was not observed (53,54).…”

Section: Cycloheximide Activates Pdr1 Indirectly Via Engagement Of It...mentioning

confidence: 99%

Redefining Pleiotropic Drug Resistance in a Pathogenic Yeast: Pdr1 Functions as a Sensor of Cellular Stresses inCandida glabrata

Gale

Pavesic

Nickels

et al. 2023

Preprint

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Candida glabratais a prominent opportunistic fungal pathogen of humans. The increasing incidence ofC. glabratainfections is attributed to both innate and acquired resistance to antifungals. Previous studies suggest the transcription factor Pdr1 and several target genes encoding ABC transporters are critical elements of pleiotropic defense against azoles and other antifungals. This study utilizesHermestransposon insertion profiling to investigate Pdr1-independent and Pdr1-dependent mechanisms that alter susceptibility to the frontline antifungal fluconazole. Several new genes were found to alter fluconazole susceptibility independent of Pdr1 (CYB5,SSK1,SSK2,HOG1,TRP1). A bZIP transcription repressor of mitochondrial function (CIN5) positively regulated Pdr1 while hundreds of genes encoding mitochondrial proteins were confirmed as negative regulators of Pdr1. The antibiotic oligomycin activated Pdr1 and antagonized fluconazole efficacy likely by interfering with mitochondrial processes inC. glabrata. Unexpectedly, disruption of many 60S ribosomal proteins also activated Pdr1, thus mimicking the effects of the mRNA translation inhibitors. Cycloheximide failed to fully activate Pdr1 in a cycloheximide-resistant Rpl28-Q38E mutant. Similarly, fluconazole failed to fully activate Pdr1 in a strain expressing a low-affinity variant of Erg11. Fluconazole activated Pdr1 with very slow kinetics that correlated with the delayed onset of cellular stress. These findings are inconsistent with the idea that Pdr1 directly senses xenobiotics and support an alternative hypothesis where Pdr1 senses cellular stresses that arise only after engagement of xenobiotics with their targets.ImportanceCandida glabratais an opportunistic pathogenic yeast that causes discomfort and death. Its incidence has been increasing because of natural defenses to our common antifungal medications. This study explores the entire genome for impacts on resistance to fluconazole. We find several new and unexpected genes can impact susceptibility to fluconazole. Several antibiotics can also alter the efficacy of fluconazole. Most importantly, we find that Pdr1 – a key determinant of fluconazole resistance – is not regulated directly through binding of fluconazole and instead is regulated indirectly by sensing the cellular stresses caused by fluconazole blockage of sterol biosynthesis. This new understanding of drug resistance mechanisms could improve the outcomes of current antifungals and accelerate the development of novel therapeutics.

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“…Terbinafine is an allylamine that inhibits squalene epoxidase, an enzyme which catalyzes the conversion of squalene to lanosterol in the ergosterol synthesis pathway. Artemisinin is an antimalarial drug which has also been reported to have fungistatic activity, but has yet to be tested against Malassezia species ( 11 – 13 ). The mechanisms of action of artemisinin against fungi are still unknown.…”

Section: Observationmentioning

confidence: 99%

Antimicrobial Susceptibility Testing for Three Malassezia Species

Rathie

Theelen

Laurence³

et al. 2023

Microbiol Spectr

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The Malassezia genus is known to be involved in a variety of skin conditions and has recently been associated with diseases such as Crohn’s disease, pancreatic ductal carcinoma, and breast cancer. This work was completed to assess susceptibility to a variety of antimicrobial drugs on three Malassezia species, in particular Malassezia restricta , which is an abundant Malassezia species both on human skin and internal organs and has been implicated in Crohn’s disease.

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Artemisinin Targets Transcription Factor PDR1 and Impairs Candida glabrata Mitochondrial Function

Cited by 8 publications

References 49 publications

Redefining pleiotropic drug resistance in a pathogenic yeast: Pdr1 functions as a sensor of cellular stresses in Candida glabrata

Redefining pleiotropic drug resistance in a pathogenic yeast: Pdr1 functions as a sensor of cellular stresses in Candida glabrata

Redefining Pleiotropic Drug Resistance in a Pathogenic Yeast: Pdr1 Functions as a Sensor of Cellular Stresses inCandida glabrata

Antimicrobial Susceptibility Testing for Three Malassezia Species

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