Cytochemical and Biochemical Studies of Yeasts After In Vitro Exposure to Miconazole

Nollin, Sonja De; Belle, H. Van; Goossens, F.; Thoné, Fred; Borgers, M.

doi:10.1128/aac.11.3.500

Cited by 86 publications

(36 citation statements)

References 42 publications

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“…6A). On the other hand, the results do not exclude a mechanism involving NO sensitization due to lanosterol 14␣-demethylase inhibition as previously suggested for clotrimazole sensitization of C. albicans to hydrogen peroxide (50) or the direct inhibition of membrane-bound ATPases and cytochrome oxidase, as well as the synthesis of mitochondrial and peroxisomal enzymes including peroxidase and catalase (8,9,30). Indeed, antibiotic synergy between imidazoles and NO-releasing diazeniumdiolates was previously reported for Candida (34) and may also be explained by NOD-independent mechanisms since the agents inhibited NOD weakly.…”

Section: Discussionmentioning

confidence: 65%

Imidazole Antibiotics Inhibit the Nitric Oxide Dioxygenase Function of Microbial Flavohemoglobin

Helmick

Fletcher

Gardner

et al. 2005

Antimicrob Agents Chemother

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Flavohemoglobins metabolize nitric oxide (NO) to nitrate and protect bacteria and fungi from NO-mediated damage, growth inhibition, and killing by NO-releasing immune cells. Antimicrobial imidazoles were tested for their ability to coordinate flavohemoglobin and inhibit its NO dioxygenase (NOD) function. Miconazole, econazole, clotrimazole, and ketoconazole inhibited the NOD activity of Escherichia coli flavohemoglobin with apparent K i values of 80, 550, 1,300, and 5,000 nM, respectively. Saccharomyces cerevisiae, Candida albicans, and Alcaligenes eutrophus enzymes exhibited similar sensitivities to imidazoles. Imidazoles coordinated the heme iron atom, impaired ferric heme reduction, produced uncompetitive inhibition with respect to O 2 and NO, and inhibited NO metabolism by yeasts and bacteria. Nevertheless, these imidazoles were not sufficiently selective to fully mimic the NO-dependent growth stasis seen with NOD-deficient mutants. The results demonstrate a mechanism for NOD inhibition by imidazoles and suggest a target for imidazole engineering.

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Section: Discussionmentioning

confidence: 65%

Imidazole Antibiotics Inhibit the Nitric Oxide Dioxygenase Function of Microbial Flavohemoglobin

Helmick

Fletcher

Gardner

et al. 2005

Antimicrob Agents Chemother

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“…Sud and Feingold (290) discovered that the fungistatic potentials of miconazole and clotrimazole were abrogated in reduced oxygen tensions. Miconazole also has been shown to adversely affect cytochrome and peroxidase activity in cells of C. albicans and Saccharomyces cerevisiae (69). Ketoconazole blocks the transport of electrons in the respiratory chain of C. albicans (273,311).…”

Section: Proposed Modes Of Action Of Antifungal Azole Derivativesmentioning

confidence: 99%

Overview of medically important antifungal azole derivatives

1988

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Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

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“…Furthermore, in fungi and yeast, azole treatment leads to an increase in the endogenous production of reactive oxygen species (ROS) (12,25). For example, in Candida albicans and Saccharomyces cerevisiae, the miconazole inhibition of cytochrome c oxidase, peroxidase, and catalase has been reported to be responsible for a high level of ROS production (3,4). It has also been reported that clotrimazole inhibition of Plasmodium falciparum hemoperoxidase leads to ROS accumulation in this protozoan pathogen (26).…”

mentioning

confidence: 99%

Binding of Azole Antibiotics to Staphylococcus aureus Flavohemoglobin Increases Intracellular Oxidative Stress

et al. 2010

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In this work, we report that flavohemoglobin contributes to the azole susceptibility of Staphylococcus aureus. We first observed that deletion of the flavohemoglobin gene leads to an increase in the viability of imidazoletreated S. aureus cells and that reversion to the wild-type phenotype occurs upon expression of flavohemoglobin from a multicopy plasmid. Further spectroscopic analyses showed that miconazole, the most efficient azole antibiotic against S. aureus, ligates to heme of both oxidized and reduced flavohemoglobin. The binding of miconazole to oxidized flavohemoglobin, with an association constant of 1.7 ؋ 10 6 M ؊1 , typical of a tight, specific binding equilibrium, results in augmentation of the superoxide production by the enzyme. These results are corroborated by in vivo studies showing that imidazole-treated S. aureus cells expressing flavohemoglobin contain a larger amount of reactive oxygen species. Moreover, it was observed that the survival of miconazole-treated S. aureus internalized by murine macrophages is higher for cells lacking flavohemoglobin. Altogether, the present data revealed that in S. aureus, flavohemoglobin enhances the antimicrobial activity of imidazoles via an increase of intracellular oxidative stress.Staphylococcus aureus is an opportunistic pathogen responsible for a large number of human infections that cause systemic diseases from a mild to life-threatening character. The increasing incidence of methicillin-resistant S. aureus (MRSA) strains observed in the past few years makes S. aureus infections a leading threat to public health, causing more deaths in the United States and Europe than human immunodeficiency virus (AIDS) (11). Like other Gram-positive bacteria, staphylococci are sensitive to imidazoles (27). Imidazoles (such as clotrimazole, miconazole, ketoconazole, and sulconazole) ( Fig. 1) represent one of the major classes of azole antifungal that are useful in the treatment of infections, including cutaneous and vaginal candidiasis (8). The activity of these antifungal drugs derives primarily from inhibition of the biosynthesis of ergosterol, an essential component of the fungal plasma membrane, at the level of lanosterol 14-alpha demethylase. Furthermore, in fungi and yeast, azole treatment leads to an increase in the endogenous production of reactive oxygen species (ROS) (12, 25). For example, in Candida albicans and Saccharomyces cerevisiae, the miconazole inhibition of cytochrome c oxidase, peroxidase, and catalase has been reported to be responsible for a high level of ROS production (3, 4). It has also been reported that clotrimazole inhibition of Plasmodium falciparum hemoperoxidase leads to ROS accumulation in this protozoan pathogen (26). For S. cerevisiae, C. albicans, and Escherichia coli, the action of imidazoles was also correlated with the inhibition of the nitric oxide (NO) scavenger activity of flavohemoglobin (7).Flavohemoglobins (Hmp) are widespread among bacteria and yeast and contain three domains: C-terminal NAD-and flavin adenine dinucleot...

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Cytochemical and Biochemical Studies of Yeasts After In Vitro Exposure to Miconazole

Cited by 86 publications

References 42 publications

Imidazole Antibiotics Inhibit the Nitric Oxide Dioxygenase Function of Microbial Flavohemoglobin

Imidazole Antibiotics Inhibit the Nitric Oxide Dioxygenase Function of Microbial Flavohemoglobin

Overview of medically important antifungal azole derivatives

Binding of Azole Antibiotics to Staphylococcus aureus Flavohemoglobin Increases Intracellular Oxidative Stress

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