scholarly journals The Production of Reactive Oxygen Species Is a Universal Action Mechanism of Amphotericin B against Pathogenic Yeasts and Contributes to the Fungicidal Effect of This Drug

2014 ◽  
Vol 58 (11) ◽  
pp. 6627-6638 ◽  
Author(s):  
Ana Cecilia Mesa-Arango ◽  
Nuria Trevijano-Contador ◽  
Elvira Román ◽  
Ruth Sánchez-Fresneda ◽  
Celia Casas ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Amphotericin B ◽  
Reactive Oxygen ◽  
Mitochondrial Respiratory Chain ◽  
Oxygen Species ◽  
Action Mechanism ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Fungicidal Effect ◽  
Killing Action

ABSTRACTAmphotericin B (AMB) is an antifungal drug that binds to ergosterol and forms pores at the cell membrane, causing the loss of ions. In addition, AMB induces the accumulation of reactive oxygen species (ROS), and although these molecules have multiple deleterious effects on fungal cells, their specific role in the action mechanism of AMB remains unknown. In this work, we studied the role of ROS in the action mechanism of AMB. We determined the intracellular induction of ROS in 44 isolates of different pathogenic yeast species (Candida albicans,Candida parapsilosis,Candida glabrata,Candida tropicalis,Candida krusei,Cryptococcus neoformans, andCryptococcus gattii). We also characterized the production of ROS in AMB-resistant isolates. We found that AMB induces the formation of ROS in all the species tested. The inhibition of the mitochondrial respiratory chain by rotenone blocked the induction of ROS by AMB and provided protection from the killing action of the antifungal. Moreover, this phenomenon was absent in strains that displayed resistance to AMB. These strains showed an alteration in the respiration rate and mitochondrial membrane potential and also had higher catalase activity than that of the AMB-susceptible strains. Consistently, AMB failed to induce protein carbonylation in the resistant strains. Our data demonstrate that the production of ROS by AMB is a universal and important action mechanism that is correlated with the fungicidal effect and might explain the low rate of resistance to the molecule. Finally, these data provide an opportunity to design new strategies to improve the efficacy of this antifungal.

scholarly journals Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elena Shekhova ◽  
Olaf Kniemeyer ◽  
Axel A. Brakhage
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Complex I ◽  
Reactive Oxygen ◽  
Antifungal Compounds ◽  
Ros Production ◽  
Oxygen Species ◽  
Content Type

ABSTRACT Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of Aspergillus fumigatus with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds.

scholarly journals Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

2015 ◽  
Vol 59 (7) ◽  
pp. 4003-4011 ◽  
Author(s):  
Ludmila Matos Baltazar ◽  
Silvia Maria Cordeiro Werneck ◽  
Betânia Maria Soares ◽  
Marcus Vinicius L. Ferreira ◽  
Danielle G. Souza ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Amphotericin B ◽  
Reactive Oxygen ◽  
Antifungal Drugs ◽  
Yeast Cells ◽  
Health Concern ◽  
Oxygen Species ◽  
Protective Function ◽  
Content Type

ABSTRACTParacoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced byParacoccidioidesspp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production byParacoccidioidesyeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI.

scholarly journals Limited Mitochondrial Capacity of Visceral Versus Subcutaneous White Adipocytes in Male C57BL/6N Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 923-933 ◽  
Author(s):  
Theresa Schöttl ◽  
Lisa Kappler ◽  
Katharina Braun ◽  
Tobias Fromme ◽  
Martin Klingenspor
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Mitochondrial Respiratory Chain ◽  
Metabolic Risk ◽  
Oxygen Species ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Fat Depot ◽  
Mitochondrial Capacity

Abstract Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. We therefore investigated whether the metabolic risk of visceral vs peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content compared with epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet (HFD) for 1 week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared with inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot.

scholarly journals Oxidative Stressors Modify the Response of Streptococcus mutans to Its Competence Signal Peptides

2017 ◽  
Vol 83 (22) ◽  
Author(s):  
Matthew De Furio ◽  
Sang Joon Ahn ◽  
Robert A. Burne ◽  
Stephen J. Hagen
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dental Caries ◽  
Signaling Pathway ◽  
Streptococcus Mutans ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Oral Biofilm ◽  
Genetic Competence ◽  
Content Type

ABSTRACTThe dental caries pathogenStreptococcus mutansis continually exposed to several types of stress in the oral biofilm environment. Oxidative stress generated by reactive oxygen species has a major impact on the establishment, persistence, and virulence ofS. mutans. Here, we combined fluorescent reporter-promoter fusions with single-cell imaging to study the effects of reactive oxygen species on activation of genetic competence inS. mutans. Exposure to paraquat, which generates superoxide anion, produced a qualitatively different effect on activation of expression of the gene for the master competence regulator, ComX, than did treatment with hydrogen peroxide (H2O2), which can yield hydroxyl radical. Paraquat suppressed peptide-mediated induction ofcomXin a progressive and cumulative fashion, whereas the response to H2O2displayed a strong threshold behavior. Low concentrations of H2O2had little effect on induction ofcomXor the bacteriocin genecipB, but expression of these genes declined sharply if extracellular H2O2exceeded a threshold concentration. These effects were not due to decreased reporter gene fluorescence. Two different threshold concentrations were observed in the response to H2O2, depending on the gene promoter that was analyzed and the pathway by which the competence regulon was stimulated. The results show that paraquat and H2O2affect theS. mutanscompetence signaling pathway differently, and that some portions of the competence signaling pathway are more sensitive to oxidative stress than others.IMPORTANCEStreptococcus mutansinhabits the oral biofilm, where it plays an important role in the development of dental caries. Environmental stresses such as oxidative stress influence the growth ofS. mutansand its important virulence-associated behaviors, such as genetic competence.S. mutanscompetence development is a complex behavior that involves two different signaling peptides and can exhibit cell-to-cell heterogeneity. Although oxidative stress is known to influenceS. mutanscompetence, it is not understood how oxidative stress interacts with the peptide signaling or affects heterogeneity. In this study, we used fluorescent reporters to probe the effect of reactive oxygen species on competence signaling at the single-cell level. Our data show that different reactive oxygen species have different effects onS. mutanscompetence, and that some portions of the signaling pathway are more acutely sensitive to oxidative stress than others.

scholarly journals The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Jiangbei Yuan ◽  
Zihan Zheng ◽  
Liting Wang ◽  
Haiying Ran ◽  
Xiangyu Tang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Listeria Monocytogenes ◽  
Membrane Proteins ◽  
Defense Mechanisms ◽  
Reactive Oxygen ◽  
Cellular Membrane ◽  
Oxygen Species ◽  
Dynein Light Chain ◽  
Mitochondrial Reactive Oxygen Species ◽  
Content Type

ABSTRACT Cellular membrane proteins are a critical part of the host defense mechanisms against infection and intracellular survival of Listeria monocytogenes. The complex spatiotemporal regulation of bacterial infection by various membrane proteins has been challenging to study. Here, using mass spectrometry analyses, we depicted the dynamic expression landscape of membrane proteins upon L. monocytogenes infection in dendritic cells. We showed that Dynein light chain 1 (Dynll1) formed a persistent complex with the mitochondrial cytochrome oxidase Cox4i1, which is disturbed by pathogen insult. We discovered that the dissociation of the Dynll1-Cox4i1 complex is required for the release of mitochondrial reactive oxygen species and serves as a regulator of intracellular proliferation of Listeria monocytogenes. Our study shows that Dynll1 is an inhibitor of mitochondrial reactive oxygen species and can serve as a potential molecular drug target for antibacterial treatment.

scholarly journals Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Lucia Xiang ◽  
Maria Fernanda Laranjeira-Silva ◽  
Fernando Y. Maeda ◽  
Jason Hauzel ◽  
Norma W. Andrews ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Macrophage Infection ◽  
Cutaneous Lesions ◽  
Signaling Mechanism ◽  
Content Type ◽  
Temporal Regulation ◽  
Metacyclic Promastigotes

ABSTRACT The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H2O2 is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H2O2. Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H2O2, generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoculation into mice. Collectively, our data support a role for APX-regulated mitochondrial H2O2 in promoting differentiation of virulent forms in both L. major and L. amazonensis. Our results also uncover a unique requirement for APX-mediated control of ROS levels for survival and successful intracellular replication of L. amazonensis.

scholarly journals Potentiation of Antibiofilm Activity of Amphotericin B by Superoxide Dismutase Inhibition

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Katrijn De Brucker ◽  
Anna Bink ◽  
Els Meert ◽  
Bruno P. A. Cammue ◽  
Karin Thevissen
Keyword(s):  
Reactive Oxygen Species ◽  
Superoxide Dismutase ◽  
Candida Albicans ◽  
Amphotericin B ◽  
Reactive Oxygen ◽  
Intracellular Reactive Oxygen Species ◽  
Superoxide Dismutases ◽  
Antibiofilm Activity ◽  
Oxygen Species ◽  
Ammonium Tetrathiomolybdate

This study demonstrates a role for superoxide dismutases (Sods) in governing tolerance ofCandida albicansbiofilms to amphotericin B (AmB). Coincubation ofC. albicansbiofilms with AmB and the Sod inhibitors N,N′-diethyldithiocarbamate (DDC) or ammonium tetrathiomolybdate (ATM) resulted in reduced viable biofilm cells and increased intracellular reactive oxygen species levels as compared to incubation of biofilm cells with AmB, DDC, or ATM alone. Hence, Sod inhibitors can be used to potentiate the activity of AmB againstC. albicansbiofilms.

Superoxide Production by the Mitochondrial Respiratory Chain

1997 ◽  
Vol 17 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Julio F. Turrens
Keyword(s):  
Reactive Oxygen Species ◽  
Respiratory Chain ◽  
Reactive Oxygen ◽  
Mitochondrial Respiratory Chain ◽  
Superoxide Production ◽  
Oxygen Species ◽  
Pathological Conditions ◽  
Superoxide Formation ◽  
Effect Of Inhibitors

This mini-review describes the role of different mitochondrial components in the formation of reactive oxygen species under normal and pathological conditions and the effect of inhibitors and uncouplers on superoxide formation.

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