Design and Synthesis of a Series of Piperazine‐1‐carboxamidine Derivatives with Antifungal Activity Resulting from Accumulation of Endogenous Reactive Oxygen Species

François, Isabelle; Thevissen, Karin; Pellens, Klaartje; Meert, Els; Heeres, Jan; Freyne, Eddy; Coesemans, Erwin; Viellevoye, Marcel; Deroose, Frederik; Martı́nez, Sonia; Pastor, Joaquı́n; Corens, David; Meerpoel, Lieven; Borgers, M.; Ausma, Jannie; Dispersyn, Gerrit D.; Cammue, Bruno P. A.

doi:10.1002/cmdc.200900249

Cited by 16 publications

(19 citation statements)

References 35 publications

(32 reference statements)

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“…Various antifungal molecules are known to induce the accumulation of ROS in susceptible yeast and fungal species (7,43,44). Significant accumulation of endogenous ROS, indicated by the fluorescent dye H 2 DCFDA, in C. albicans biofilm cells was observed subsequent to 24-h treatment with TrcA, TrcB, and TrcC compared to the untreated cells (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…The relationship between endogenous ROS generation in C. albicans and tyrocidine antifungal activity was investigated using the antioxidant ascorbic acid. The influence of 10.0 mM ascorbic acid on the biofilm eradication and ROS induction activity of 100.0 M TrcA, TrcB, and TrcC was determined (43,44). Citric acid served as a pH control.…”

Section: Assay For Determination Of Endogenous Rosmentioning

confidence: 99%

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Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

Troskie

Rautenbach

Delattin

et al. 2014

Antimicrob Agents Chemother

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dTyrocidines are cationic cyclodecapeptides from Bacillus aneurinolyticus that are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonic Candida albicans in the low-micromolar range. These tyrocidines also prevented C. albicans biofilm formation in vitro. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of mature C. albicans biofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using a Caenorhabditis elegans infection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment.

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Section: Resultsmentioning

confidence: 95%

Section: Assay For Determination Of Endogenous Rosmentioning

confidence: 99%

Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

Troskie

Rautenbach

Delattin

et al. 2014

Antimicrob Agents Chemother

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“…Furthermore, metergoline, DHS and phytosphingosine induce apoptosis in Candida krusei [71] and Aspergillus nidulans, respectively [72]. For the DHS analogs and the piperazine-1-carboxyamidine derivatives, a direct correlation between antifungal activity and ROS accumulation was found using the antioxidant ascorbic acid [73,74].…”

Section: Novel Ros-inducing Antifungal Agentsmentioning

confidence: 97%

“…that are reported to induce ROS are 7-chlorotetrazolo-[5,1-c]benzo[1,2,4]triazine [68][69][70], the serotoninereceptor antagonist metergoline [71], dihydrosphingosine (DHS; and its analogs) and phytosphingosine [72,73], piperazine-1-carboxyamidine derivatives [74] and hydroxypyridones [75]. Furthermore, metergoline, DHS and phytosphingosine induce apoptosis in Candida krusei [71] and Aspergillus nidulans, respectively [72].…”

Section: Novel Ros-inducing Antifungal Agentsmentioning

confidence: 98%

Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms

2013

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Invasive fungal infections are associated with very high mortality rates ranging from 20-90% for opportunistic fungal pathogens such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungal resistance to antimycotic treatment can be genotypic (due to resistant strains) as well as phenotypic (due to more resistant fungal lifestyles, such as biofilms). With regard to the latter, biofilms are considered to be critical in the development of invasive fungal infections. However, there are only very few antimycotics, such as miconazole (azoles), echinocandins and liposomal formulations of amphotericin B (polyenes), which are also effective against fungal biofilms. Interestingly, these antimycotics all induce reactive oxygen species (ROS) in fungal (biofilm) cells. This review provides an overview of the different classes of antimycotics and novel antifungal compounds that induce ROS in fungal planktonic and biofilm cells. Moreover, different strategies to further enhance the antibiofilm activity of such ROS-inducing antimycotics will be discussed.

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“…In contrast to other azole-type antifungals, a fungicidal effect of ROS-inducing miconazole against biofilms of several C. albicans strains was reported when used in high (millimolar) concentrations1011, but the causal relationship between induction of ROS and fungicidal activity remains under debate1314. Interestingly, targeting C. albicans’ oxidative defence system to sustain high ROS levels reportedly enhances the fungicidal activity of ROS-inducing antifungals611131516.…”

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confidence: 99%

Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms

Cremer

Brucker

Staes

et al. 2016

Sci Rep

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We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing. Our aim was to identify molecular pathways employed by biofilm cells of this pathogen to resist action of the commonly used antifungal miconazole. As expected, genes involved in sterol biosynthesis and genes encoding drug efflux pumps were highly induced in biofilm cells upon miconazole treatment. Other processes were affected as well, including the electron transport chain (ETC), of which eight components were transcriptionally downregulated. Within a diverse set of 17 inhibitors/inducers of the transcriptionally affected pathways, the ETC inhibitors acted most synergistically with miconazole against C. albicans biofilm cells. Synergy was not observed for planktonically growing C. albicans cultures or when biofilms were treated in oxygen-deprived conditions, pointing to a biofilm-specific oxygen-dependent tolerance mechanism. In line, a correlation between miconazole’s fungicidal action against C. albicans biofilm cells and the levels of superoxide radicals was observed, and confirmed both genetically and pharmacologically using a triple superoxide dismutase mutant and a superoxide dismutase inhibitor N-N′-diethyldithiocarbamate, respectively. Consequently, ETC inhibitors that result in mitochondrial dysfunction and affect production of reactive oxygen species can increase miconazole’s fungicidal activity against C. albicans biofilm cells.

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Design and Synthesis of a Series of Piperazine‐1‐carboxamidine Derivatives with Antifungal Activity Resulting from Accumulation of Endogenous Reactive Oxygen Species

Cited by 16 publications

References 35 publications

Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms

Stimulation of superoxide production increases fungicidal action of miconazole against Candida albicans biofilms

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