title: In vitro effect of malachite green on Candida albicans involves multiple pathways and transcriptional regulators UPC2 and STP2.
abstract: In this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively kill Candida albicans and non-C. albicans species. We have demonstrated that Candida cells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC(50)], 100 ng ml(-1)) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment of C. albicans cells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally that Candida cells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulators UPC2 (regulating ergosterol biosynthesis and azole resistance) and STP2 (regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candida effects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.
authors: Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors: Sanjiveeni
authors: S
authors: Dhamgaye
authors: Frederic
authors: F
authors: Devaux
authors: Raman
authors: R
authors: Manoharlal
authors: Patrick
authors: P
authors: Vandeputte
authors: Abdul Haseeb
authors: AH
authors: Shah
authors: Ashutosh
authors: A
authors: Singh
authors: Corinne
authors: C
authors: Blugeon
authors: Dominique
authors: D
authors: Sanglard
authors: Rajendra
authors: R
authors: Prasad
mesh_terms: D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D025141:Drug Resistance, Fungal; D004875:Ergosterol / Q000378:metabolism; D005285:Fermentation; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects* / Q000235:genetics; D007501:Iron / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012394:Rosaniline Dyes / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D059467:Transcriptome
chemical_list: D026905:Amino Acid Transport Systems; D000935:Antifungal Agents; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D012394:Rosaniline Dyes; D015534:Trans-Activators; D014157:Transcription Factors; C005095:malachite green; D007501:Iron; D004875:Ergosterol