scholarly journals Photoinactivation of catalase sensitizes Candida albicans and Candida auris to ROS-producing agents and immune cells

2021 ◽  
Author(s):  
Pu-Ting Dong ◽  
Yuewei Zhan ◽  
Sebastian Jusuf ◽  
Jie Hui ◽  
Zeina Dagher ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Blue Light ◽  
Optical Switch ◽  
Multidrug Resistant ◽  
Fungal Species ◽  
Candida Auris ◽  
Fungal Cell ◽  
Wide Range ◽  
Inactivation Mechanism ◽  
Macrophage Killing

Nearly all organisms found in nature have evolved and developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme-containing tetramer protein expressed in a broad range of aerobic fungi, has been utilized as an essential enzymatic ROS detoxifying mechanism, and shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal cell survival and host invasion. Here, we demonstrate that catalase inactivation with blue light renders fungal cells highly susceptible to ROS attack, thus resembling a 'strength-to-weakness optical switch'. To unveil catalase as the underlying molecular target of blue light and its inactivation mechanism, we systematically compared wild-type Candida albicans to a catalase-deficient mutant strain for susceptibility to ROS in the absence/presence of 410 nm treatment. Upon testing on a wide range of fungal species and strains, we found that intracellular catalase could be effectively and universally inactivated by 410 nm blue light. We find that the photoinactivation of catalase in combination with ROS-generating agents is highly effective and potent in achieving full eradication of multiple fungal species and strains, including multiple clinical strains of Candida auris, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a Candida albicans-induced mouse model of skin abrasion. Taken together, our findings offer a novel catalase-photoinactivation approach to address multidrug-resistant Candida infections.

scholarly journals Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 539
Author(s):  
Mahmoud Ghannoum ◽  
Maiken Cavling Arendrup ◽  
Vishnu P. Chaturvedi ◽  
Shawn R. Lockhart ◽  
Thomas S. McCormick ◽  
...  
Keyword(s):  
Antifungal Agent ◽  
Complete Response ◽  
Clinical Results ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Open Label ◽  
Candida Spp ◽  
Fungal Cell ◽  
Novel Treatments

Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

scholarly journals Photoinactivation of Catalase Sensitizes Wide-Ranging Bacteria to ROS-Producing Agents and Immune Cells

2021 ◽  
Author(s):  
Pu-Ting Dong ◽  
Sebastian Jusuf ◽  
Jie Hui ◽  
Yuewei Zhan ◽  
Yifan Zhu ◽  
...  
Keyword(s):  
Blue Light ◽  
Immune Cells ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Aerobic Bacteria ◽  
Oxygen Species ◽  
Wild Type ◽  
Planktonic Bacteria ◽  
Wide Range ◽  
Molecular Components

Bacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing in bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2 and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2 synergistically eliminate a wide range of catalase-positive planktonic bacteria and P. aeruginosa inside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using a Pseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy against multidrug-resistant bacterial infections.

scholarly journals Gut-Evolved Candida albicans Induces Metabolic Changes in Neutrophils

2021 ◽  
Vol 11 ◽  
Author(s):  
Jose Antonio Reales-Calderon ◽  
Gloria H. W. Tso ◽  
Alrina S. M. Tan ◽  
Pei Xiang Hor ◽  
Julia Böhme ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Nk Cells ◽  
Bone Marrow Cells ◽  
Metabolic Changes ◽  
Immune Memory ◽  
Cellular Mechanisms ◽  
Fungal Cell ◽  
Mouse Splenocytes ◽  
Trained Immunity ◽  
Wide Range

Serial passaging of the human fungal pathogen Candida albicans in the gastrointestinal tract of antibiotics-treated mice selects for virulence-attenuated strains. These gut-evolved strains protect the host from infection by a wide range of pathogens via trained immunity. Here, we further investigated the molecular and cellular mechanisms underlying this innate immune memory. Both Dectin-1 (the main receptor for β-glucan; a well-described immune training molecule in the fungal cell wall) and Nod2 (a receptor described to mediate BCG-induced trained immunity), were redundant for the protection induced by gut-evolved C. albicans against a virulent C. albicans strain, suggesting that gut-evolved C. albicans strains induce trained immunity via other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved C. albicans resulted in an expansion of neutrophils and a reduction in natural killer (NK) cells, but no significant numeric changes in monocytes, macrophages or dendritic cell populations. Systemic depletion of phagocytes or neutrophils, but not of macrophages or NK cells, reduced protection mediated by gut-evolved C. albicans. Splenocytes and bone marrow cells of mice immunized with gut-evolved C. albicans demonstrated metabolic changes. In particular, splenic neutrophils displayed significantly elevated glycolytic and respiratory activity in comparison to those from mock-immunized mice. Although further investigation is required for fully deciphering the trained immunity mechanism induced by gut-evolved C. albicans strains, this data is consistent with the existence of several mechanisms of trained immunity, triggered by different training stimuli and involving different immune molecules and cell types.

scholarly journals Antifungal Resistance: Specific Focus on Multidrug Resistance in Candida auris and Secondary Azole Resistance in Aspergillus fumigatus

2018 ◽  
Vol 4 (4) ◽  
pp. 129 ◽  
Author(s):  
Sevtap Arikan-Akdagli ◽  
Mahmoud Ghannoum ◽  
Jacques Meis
Keyword(s):  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Multidrug Resistant ◽  
Fungal Species ◽  
Antifungal Resistance ◽  
Current Status ◽  
Clinical Implications ◽  
Azole Resistance ◽  
Candida Auris

Antifungal resistance is a topic of concern, particularly for specific fungal species and drugs. Among these are the multidrug-resistant Candida auris and azole-resistant Aspergillus fumigatus. While the knowledge on molecular mechanisms of resistance is now accumulating, further data are also available for the clinical implications and the extent of correlation of in vitro resistance to clinical outcomes. This review article summarizes the epidemiology of C. auris infections, animal models focusing on the activity of novel antifungal compounds in C. auris infections, virulence factors, and the mechanisms of antifungal resistance for this multi-resistant Candida species. Regarding A. fumigatus, the significance of azoles in the treatment of A. fumigatus infections, reference methods available for the detection of resistance in vitro, molecular mechanisms of secondary azole resistance, routes of acquisition, and clinical implications of in vitro resistance are covered to provide guidance for the current status of azole resistance in A. fumigatus.

scholarly journals N-Acetylglucosamine (GlcNAc) Sensing, Utilization, and Functions in Candida albicans

2020 ◽  
Vol 6 (3) ◽  
pp. 129 ◽  
Author(s):  
Han Du ◽  
Craig L. Ennis ◽  
Aaron D. Hernday ◽  
Clarissa J. Nobile ◽  
Guanghua Huang
Keyword(s):  
Candida Albicans ◽  
Fungal Species ◽  
Phenotypic Switch ◽  
Fungal Cell ◽  
The Past ◽  
Amide Derivative ◽  
Major Nutrient ◽  
Morphological Transitions ◽  
Opportunistic Fungal Pathogen ◽  
Eukaryotic Organisms

The sensing and efficient utilization of environmental nutrients are critical for the survival of microorganisms in environments where nutrients are limited, such as within mammalian hosts. Candida albicans is a common member of the human microbiota as well as an opportunistic fungal pathogen. The amide derivative sugar N-acetlyglucosamine (GlcNAc) is an important signaling molecule for C. albicans that could be a major nutrient source for this fungus in host settings. In this article, we review progress made over the past two decades on GlcNAc utilization, sensing, and functions in C. albicans and its related fungal species. GlcNAc sensing and catabolic pathways have been intensively studied in C. albicans. The C. albicans protein Ngt1 represents the first identified GlcNAc-specific transporter in eukaryotic organisms. In C. albicans, GlcNAc not only induces morphological transitions including the yeast to hyphal transition and the white to opaque phenotypic switch, but it also promotes fungal cell death. The Ras-cAMP/PKA signaling pathway plays critical roles in regulating these processes. Given the importance of GlcNAc sensing and utilization in C. albicans, targeting GlcNAc associated pathways and key pathway components could be promising in the development of new antifungal strategies.

scholarly journals Cathelicidin-inspired antimicrobial peptides as novel antifungal compounds

2020 ◽  
Vol 58 (8) ◽  
pp. 1073-1084
Author(s):  
Martin van Eijk ◽  
Stephanie Boerefijn ◽  
Lida Cen ◽  
Marisela Rosa ◽  
Marnix J H Morren ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Metabolic Activity ◽  
Fungal Infections ◽  
Fungal Species ◽  
Antifungal Compounds ◽  
Candida Auris ◽  
Low Concentrations ◽  
Wide Range ◽  
Eskape Pathogens ◽  
Near Future

Abstract Fungal infections in humans are increasing worldwide and are currently mostly treated with a relative limited set of antifungals. Resistance to antifungals is increasing, for example, in Aspergillus fumigatus and Candida auris, and expected to increase for many medically relevant fungal species in the near future. We have developed and patented a set of cathelicidin-inspired antimicrobial peptides termed ‘PepBiotics’. These peptides were initially selected for their bactericidal activity against clinically relevant Pseudomonas aeruginosa and Staphylococcus aureus isolates derived from patients with cystic fibrosis and are active against a wide range of bacteria (ESKAPE pathogens). We now report results from studies that were designed to investigate the antifungal activity of PepBiotics against a set of medically relevant species encompassing species of Aspergillus, Candida, Cryptococcus, Fusarium, Malassezia, and Talaromyces. We characterized a subset of PepBiotics and show that these peptides strongly affected metabolic activity and/or growth of a set of medically relevant fungal species, including azole-resistant A. fumigatus isolates. PepBiotics showed a strong inhibitory activity against a large variety of filamentous fungi and yeasts species at low concentrations (≤1 μM) and were fungicidal for at least a subset of these fungal species. Interestingly, the concentration of PepBiotics required to interfere with growth or metabolic activity varied between different fungal species or even between isolates of the same fungal species. This study shows that PepBiotics display strong potential for use as novel antifungal compounds to fight a large variety of clinically relevant fungal species.

scholarly journals Oxadiazole-Containing Macrocyclic Peptides Potentiate Azole Activity against Pathogenic Candida Species

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Nicole M. Revie ◽  
Nicole Robbins ◽  
Luke Whitesell ◽  
John R. Frost ◽  
Solomon D. Appavoo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Candida Auris ◽  
Peptide Backbone ◽  
Fungal Cell ◽  
Content Type ◽  
Development Of Resistance ◽  
Macrocyclic Peptides ◽  
Novel Therapeutic Strategies

ABSTRACT Opportunistic pathogens of the genus Candida reign as the leading cause of mycotic disease and are associated with mortality rates greater than 40%, even with antifungal intervention. This is in part due to the limited arsenal of antifungals available to treat systemic fungal infections. Azoles have been the most widely deployed class of antifungal drug for decades and function by targeting the biosynthesis of ergosterol, a key component of the fungal cell membrane. However, their utility is compromised by their fungistatic nature, which favors the development of resistance. Combination therapy has the potential to confer enhanced efficacy as well as mitigate the evolution of resistance. Previously, we described the generation of structurally diverse macrocyclic peptides with a 1,3,4-oxadiazole and an endocyclic amine grafted within the peptide backbone. Importantly, this noncanonical backbone displayed high membrane permeability, an important attribute for compounds that need to permeate across the fungal cell wall and membrane in order to reach their intracellular target. Here, we explored the bioactivity of this novel chemical scaffold on its own and in combination with the azole fluconazole. Although few of the oxadiazole-containing macrocyclic peptides displayed activity against Candida albicans on their own, many increased the efficacy of fluconazole, resulting in a synergistic combination that was independent of efflux inhibition. Interestingly, these molecules also enhanced azole activity against several non-albicans Candida species, including the azole-resistant pathogens Candida glabrata and Candida auris. This work characterizes a novel chemical scaffold that possesses azole-potentiating activity against clinically important Candida species. IMPORTANCE Fungal infections, such as those caused by pathogenic Candida species, pose a serious threat to human health. Treating these infections relies heavily on the use of azole antifungals; however, resistance to these drugs develops readily, demanding novel therapeutic strategies. This study characterized the antifungal activity of a series of molecules that possess unique chemical attributes and the ability to traverse cellular membranes. We observed that many of the compounds increased the activity of the azole fluconazole against Candida albicans, without blocking the action of drug efflux pumps. These molecules also increased the efficacy of azoles against other Candida species, including the emerging azole-resistant pathogen Candida auris. Thus, we describe a novel chemical scaffold with broad-spectrum bioactivity against clinically important fungal pathogens.

scholarly journals A second generation fungerp analog SCY-247, shows potent in vitro activity against Candida auris and other clinically relevant fungal isolates

2020 ◽  
pp. AAC.01988-20
Author(s):  
Sherman Chu ◽  
Lisa Long ◽  
Rania Sherif ◽  
Thomas S. McCormick ◽  
Katyna Borroto-Esoda ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Second Generation ◽  
Fungal Infections ◽  
Parent Compound ◽  
Fungal Species ◽  
Antifungal Compound ◽  
Candida Auris ◽  
Fungal Cell ◽  
Antifungal Properties

Due to the increase of antifungal drug resistance and difficulties associated with drug administration, new antifungal agents for invasive fungal infections are needed. SCY-247 is a second-generation fungerp antifungal compound that interferes with the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan. We conducted an extensive antifungal screen of SCY-247 against yeast and mold strains compared with the parent compound ibrexafungerp (IBX, formerly SCY-078) to evaluate the in vitro antifungal properties of SCY-247. SCY-247 demonstrated similar activity to IBX against all of the organisms tested. Moreover, SCY-247 showed a higher percentage of fungicidal activity against the panel of yeast and mold isolates compared to IBX. Notably, SCY-247 showed considerable antifungal properties against numerous strains of Candida auris. Additionally, SCY-247 retained its antifungal activity when evaluated in the presence of synthetic urine, indicating that SCY-247 maintains activity and structural stability under environments with decreased pH levels. Finally, a time-kill study showed SCY-247 has potent anti-Candida, Aspergillus, and Scedosporium activity. In summary, SCY-247 has potent antifungal activity against various fungal species, indicating that further studies on this fungerp analog are warranted.

scholarly journals Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Makoto Sumiyoshi ◽  
Taiga Miyazaki ◽  
Juliann Nzembi Makau ◽  
Satoshi Mizuta ◽  
Yoshimasa Tanaka ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Drug Exposure ◽  
Growth Conditions ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Ion Concentration ◽  
Candida Auris ◽  
Fungal Cell ◽  
Ionic Solutions ◽  
Glucose Water

Abstract Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-d-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.

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