The fungicidal effectiveness of 2-Chloro-3-hydrazinylquinoxaline, a newly developed quinoxaline derivative, against Candida species.

BACKGROUND: Candida represents a prevalent fungal infection, notable for its substantial implications on morbidity and mortality rates. In the landscape of prospective treatments, quinoxaline derivatives emerge as a category of compact compounds exhibiting notable potential in addressing infections. These derivatives showcase promising antimicrobial efficacy coupled with favorable pharmacokinetic and safety characteristics. AIMS: The central aim of this investigation was to examine the antifungal characteristics of 2-Chloro-3-hydrazinylquinoxaline against diverse strains of Candida and Aspergillus in vitro. Additionally, we endeavored to assess the in vivo efficacy of 2-Chloro-3-hydrazinylquinoxaline using a murine model for oral candidiasis induced by C. albicans cells ATCC 10231. RESULTS: 2-Chloro-3-hydrazinylquinoxaline demonstrated noteworthy effectiveness when tested against various reference strains of Candida species. It exhibited heightened efficacy, particularly against Candida krusei isolates. However, its performance against Candida albicans, Candida tropicalis, Candida glabrata, Candida parapsilosis, and Candida auris isolates exhibited variability. Notably, 2-Chloro-3-hydrazinylquinoxaline manifests variable efficacy against Aspergillus fumigatus, Aspergillus niger, Aspergillus terreus and Aspergillus flavus and no effect against Aspergillus brasiliensis. In a murine model, 2-Chloro-3-hydrazinylquinoxaline exhibited significant efficacy in combating the C. albicans cells ATCC 10231 strain, underscoring its potential as a viable treatment option. CONCLUSION: 2-Chloro-3-hydrazinylquinoxaline has demonstrated substantial potential in effectively addressing various Candida and Aspergillus species, showcasing dual attributes of antifungal and anti-inflammatory properties. However, to attain a more comprehensive understanding of its therapeutic capabilities, further investigations, incorporating additional tests and experiments, are imperative.

Exploring the Biofilm Inhibition Potential of a Novel Phytic Acid-Crosslinked Chitosan Nanoparticle: In Vitro and In Vivo Investigations.

The primary factor underlying the virulence of Candida albicans is its capacity to form biofilms, which in turn leads to recurrent complications. Over-the-counter antifungal treatments have proven ineffective in eliminating fungal biofilms and the inflammatory cytokines produced during fungal infections. Chitosan nanoparticles offer broad and versatile therapeutic potential as both antifungal agents and carriers for antifungal drugs to combat biofilm-associated Candida infections. In our study, we endeavoured to develop chitosan nanoparticles utilising chitosan and the antifungal crosslinker phytic acid targeting C. albicans. Phytic acid, known for its potent antifungal and anti-inflammatory properties, efficiently crosslinks with chitosan. The nanoparticles were synthesised using the ionic gelation technique and subjected to analyses including Fourier transform infrared spectroscopy, dynamic light scattering, and zeta potential analysis. The synthesised nanoparticles exhibited dimensions with a diameter (Dh) of 103 ± 3.9 nm, polydispersity index (PDI) of 0.33, and zeta potential (ZP) of 37 ± 2.5 mV. These nanoparticles demonstrated an antifungal effect with a minimum inhibitory concentration (MIC) of 140 ± 2.2 µg/mL, maintaining cell viability at approximately 90% of the MIC value and reducing cytokine levels. Additionally, the nanoparticles reduced ergosterol content and exhibited a 62% ± 1.2 reduction in biofilm susceptibility, as supported by colony-forming unit (CFU) and XTT assays-furthermore, treatment with nanoparticles reduced exopolysaccharide production and decreased secretion of aspartyl protease by C. albicans. Our findings suggest that the synthesised nanoparticles effectively combat Candida albicans infections. In vivo studies conducted on a mouse model of vaginal candidiasis confirmed the efficacy of the nanoparticles in combating fungal infections in vivo.

Antifungal activity of human antimicrobial peptides targeting apoptosis in Candida auris.

Introduction. Innovative antifungal therapies are of crucial importance to combat the potentially life-threatening infections linked to the multidrug-resistant fungal pathogen Candida auris. Induction of regulated cell death, apoptosis, could provide an outline for future therapeutics. Human antimicrobial peptides (AMPs), well-known antifungal compounds, have shown the ability to induce apoptosis in pathogenic fungi.Hypothesis/Gap Statement . Although it is known that AMPs possess antifungal activity against C. auris, their ability to induce apoptosis requires further investigations.Aim. This study evaluated the effects of AMPs on the induction of apoptosis in C. auris.Methods. Human neutrophil peptide-1 (HNP-1), human ß-Defensins-3 (hBD-3) and human salivary histatin 5 (His 5) were assessed against two clinical C. auris isolates. Apoptosis hallmarks were examined using FITC-Annexin V/PI double labelling assay and terminal deoxynucleotidyl transferase deoxynucleotidyl transferase nick-end labelling (TUNEL) to detect phosphatidylserine externalization and DNA fragmentation, respectively. Then, several intracellular triggers were studied using JC-10 staining, spectrophotometric assay and 2',7'-dichlorofluorescin diacetate staining to measure the mitochondrial membrane potential, cytochrome-c release and reactive oxygen species (ROS) production, respectively.Results and conclusion. FITC-Annexin V/PI staining and TUNEL analysis revealed that exposure of C. auris cells to HNP-1 and hBD-3 triggered both early and late apoptosis, while His 5 caused significant necrosis. Furthermore, HNP-1 and hBD-3 induced significant mitochondrial membrane depolarization, which resulted in substantial cytochrome c release. In contrast to His 5, which showed minimal mitochondrial depolarization and no cytochrome c release. At last, all peptides significantly increased ROS production, which is related to both types of cell death. Therefore, these peptides represent promising and effective antifungal agents for treating invasive infections caused by multidrug-resistant C. auris.

Optimization of the antifungal properties of the bacterial peptide EntV by variant analysis.

Fungal resistance to commonly used medicines is a growing public health threat, and there is a dire need to develop new classes of antifungals. We previously described a peptide produced by Enterococcus faecalis, EntV, that restricts Candida albicans to a benign form rather than having direct fungicidal activity. Moreover, we showed that one 12-amino acid (aa) alpha helix of this peptide retained full activity, with partial activity down to the 10aa alpha helix. Using these peptides as a starting point, the current investigation sought to identify the critical features necessary for antifungal activity and to screen for new variants with enhanced activity using both biofilm and C. elegans infection assays. First, the short peptides were screened for residues with critical activity by generating alanine substitutions. Based on this information, we used synthetic molecular evolution (SME) to rationally vary the specific residues of the 10aa variant in combination to generate a library that was screened to identify variants with more potent antifungal activity than the parent template. Five gain-of-function peptides were identified. Additionally, chemical modifications to the peptides to increase stability, including substitutions of D-amino acids and hydrocarbon stapling, were investigated. The most promising peptides were additionally tested in mouse models of oropharyngeal and systemic candidiasis where their efficacy in preventing infection was demonstrated. The expectation is that these discoveries will contribute to the development of new therapeutics in the fight against antimicrobial resistant fungi. IMPORTANCE: Since the early 1980s, the incidence of disseminated life-threatening fungal infections has been on the rise. Worldwide, Candida and Cryptococcus species are among the most common agents causing these infections. Simultaneously, with this rise of clinical incidence, there has also been an increased prevalence of antifungal resistance, making treatment of these infections very difficult. For example, there are now strains of Candida auris that are resistant to all three classes of currently used antifungal drugs. In this study, we report on a strategy that allows for the development of novel antifungal agents by using synthetic molecular evolution. These discoveries demonstrate that the enhancement of antifungal activity from naturally occurring peptides is possible and can result in clinically relevant agents that have efficacy in multiple in vivo models as well as the potential for broad-spectrum activity.

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

The inhibitory effects of carvacrol, nystatin, and their combination on oral candidiasis isolates.

BACKGROUND: Candida, a common oral microbiota, can cause opportunistic fungal infections. With rising Candida infections and limited effective antifungals, new treatments are needed. This study investigates carvacrol essential oil's effect on oral candidiasis, alone and with nystatin, compared to nystatin alone. MATERIALS AND METHODS: In this study, oral samples were collected from dental clinic patients, especially denture users. The presence of Candida was confirmed and cultured from these samples. Candidiasis was detected by observing Candida colonies. Drug sensitivity was tested on 100 positive samples. The minimum concentration of inhibition and lethality of each isolate was evaluated using nystatin and carvacrol. The results were compared using two-way analysis of variance. Finally, the minimum inhibitory concentration (MIC) of nystatin and carvacrol was calculated individually and in combination. RESULTS: The present study found that Candida albicans and non-albicans species were equally prevalent. Carvacrol showed significant biological activity against all Candida species, with an average MTT of 50.01%. The average MIC value of carvacrol was 24.96 µg/ml, indicating its potential to inhibit Candida growth. The mean Minimum Fungicidal Concentration (MFC) value of carvacrol was 23.48 µg/ml, suggesting its effectiveness in killing the fungi. CONCLUSION: The study's findings reveal that the MIC of carvacrol was significantly lower than that of nystatin and the combination of nystatin and carvacrol. This suggests that carvacrol holds potential as an effective herbal remedy for candidiasis.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 µg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+ channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2 will be further investigated as a promising candidate.

Biomimetic and multifunctional nanocomposites for precision fungi theranostics.

Fungi infection is a serious threat to public health, but an effective antifungal strategy remains a challenge. Herein, a biomimetic nanocomposite with multifunctionalities, including fungi diagnosis, antifungal adhesion, precise fungi elimination, and cytokine sequestration, is constructed for battling Candida albicans (C. albicans) infection. By screening a range of cells, we find that the polarized macrophage cells have the strongest binding tendency toward C. albicans. Thus, their membranes were exfoliated to camouflage UCNPs and then decorated with photosensitizers (methylene blue, MB) and DNA sensing elements. The resulting nanocomposite can tightly bind to fungal surfaces, promote DNA recognition, and squeeze pro-inflammatory cytokines to relieve inflammation. Consequently, this nanocomposite can detect C. albicans with enhanced sensitivity and precisely eliminate fungal cells through photodynamic therapy with minimal phototoxicity because of its switchable fluorescence behavior. The developed nanocomposite with good biocompatibility achieves a satisfactory diagnostic and therapeutic effect in a C. albicans-infected mouse model, which offers a unique approach to fight fungi infection.

Robust Fluorometric Aptamer Assay for Direct and Rapid Detection of Clinical Isolates of Candida spec.

Infections caused by yeasts of the genus Candida are likely to occur not only in immunocompromised patients but also in healthy individuals, leading to infections of the gastrointestinal tract, urinary tract, and respiratory tract. Due to the rapid increase in the frequency of reported Candidiasis cases in recent years, diagnostic research has become the subject of many studies, and therefore, we developed a polyclonal aptamer library-based fluorometric assay with high specificity and affinity towards Candida spec. to quantify the pathogens in clinical samples with high sensitivity. We recently obtained the specific aptamer library R10, which explicitly recognized Candida and evolved it by mimicking an early skin infection model caused by Candida using the FluCell-SELEX system. In the follow-up study presented here, we demonstrate that the aptamer library R10-based bioassay specifically recognizes invasive clinical Candida isolates, including not only C. albicans but also strains like C. tropcialis, C. krusei, or C. glabrata. The next-generation fluorometric bioassay presented here can reliably and easily detect an early Candida infection and could be used for further clinical research or could even be developed into a full in vitro diagnostic tool.

Modeling of intravenous caspofungin administration using an intestine-on-chip reveals altered Candida albicans microcolonies and pathogenicity.

Candida albicans is a commensal yeast of the human intestinal microbiota that, under predisposing conditions, can become pathogenic and cause life-threatening systemic infections (candidiasis). Fungal-host interactions during candidiasis are commonly studied using conventional 2D in vitro models, which have provided critical insights into the pathogenicity. However, microphysiological models with a higher biological complexity may be more suitable to mimic in vivo-like infection processes and antifungal drug efficacy. Therefore, a 3D intestine-on-chip model was used to investigate fungal-host interactions during the onset of invasive candidiasis and evaluate antifungal treatment under clinically relevant conditions. By combining microbiological and image-based analyses we quantified infection processes such as invasiveness and fungal translocation across the epithelial barrier. Additionally, we obtained novel insights into fungal microcolony morphology and association with the tissue. Our results demonstrate that C. albicans microcolonies induce injury to the epithelial tissue by disrupting apical cell-cell contacts and causing inflammation. Caspofungin treatment effectively reduced the fungal biomass and induced substantial alterations in microcolony morphology during infection with a wild-type strain. However, caspofungin showed limited effects after infection with an echinocandin-resistant clinical isolate. Collectively, this organ-on-chip model can be leveraged for in-depth characterization of pathogen-host interactions and alterations due to antimicrobial treatment.

Antifungal activity of ruthenium (II) complex combined with fluconazole against drug-resistant Candida albicans in vitro and its anti-invasive infection in vivo.

With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs. Accordingly, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN)2 (bpm)] (PF6)2 (N-N = 2,2'-bipyridine) (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2'-bipyrimidine) and studied their antifungal activities. Ru3 alone had no effect on the drug-resistant strains, but Ru3 combined with fluconazole (FLC) exhibited significant antifungal activity on drug-resistant strains. A high-dose combination of Ru3 and FLC exhibited direct fungicidal activity by promoting the accumulation of reactive oxygen species and damaging the cellular structure of C. albicans. Additionally, the combination of Ru3 and FLC demonstrated potent antifungal efficacy in vivo in a mouse model of invasive candidiasis. Moreover, the combination significantly improved the survival state of mice, restored their immune systems, and reduced renal injury. These findings could provide ideas for the development of ruthenium (II) complexes as novel antifungal agents for drug-resistant microbial stains.

Discovery of New Tricyclic Oxime Sampangine Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcosis and Candidiasis.

Cryptococcus neoformans (C. neoformans) and Candida albicans (C. albicans) are classified as the critical priority groups among the pathogenic fungi, highlighting the urgent need for developing more effective antifungal therapies. On the basis of antifungal natural product sampangine, herein, a series of tricyclic oxime and oxime ether derivatives were designed. Among them, compound WZ-2 showed excellent inhibitory activity against C. neoformans (MIC80 = 0.016 µg/mL) and synergized with fluconazole to treat resistant C. albicans (FICI = 0.078). Interestingly, compound WZ-2 effectively inhibited virulence factors (e.g., capsule, biofilm, and yeast-to-hypha morphological transition), suggesting the potential to overcome drug resistance. In a mouse model of cryptococcal meningitis, compound WZ-2 (5 mg/kg) effectively reduced the brain C. neoformans H99 burden. Furthermore, compound WZ-2 alone and its combination with fluconazole also significantly reduced the kidney burden of the drug-resistant strain (0304103) and sensitive strain (SC5314) of C. albicans.

Chronic disseminated candidiasis in a patient with acute leukemia - an illustrative case and brief review for clinicians.

Chronic disseminated candidiasis (CDC) is a severe but rarely seen fungal infection presenting in patients with hematologic malignancies after a prolonged duration of neutropenia. A high index of suspicion is required to diagnose CDC as standard culture workup is often negative. While tissue biopsy is the gold standard of diagnosis, it is frequently avoided in patients with profound cytopenias and increased bleeding risks. A presumptive diagnosis can be made in patients with recent neutropenia, persistent fevers unresponsive to antibiotics, imaging findings of hypoechoic, non-rim enhancing target-like lesions in the spleen and liver, and mycologic evidence. Here, we describe the case of an 18-year-old woman with relapsed B-cell acute lymphoblastic leukemia treated with re-induction chemotherapy who subsequently developed CDC with multi-organ involvement. The diagnosis was made based on clinical and radiologic features with positive tissue culture from a skin nodule and hepatic lesion. The patient was treated for a total course of 11 months with anti-fungal therapy, most notably amphotericin B and micafungin, and splenectomy. After initial diagnosis, the patient was monitored with monthly CT abdomen imaging that showed disease control after 5 months of anti-fungal therapy and splenectomy. The diagnosis, treatment, and common challenges of CDC are outlined here to assist with better understanding, diagnosis, and treatment of this rare condition.

Clinical evaluation of antifungal de-escalation in Candida infections: A systematic review and meta-analysis.

OBJECTIVES: De-escalation (DES) from echinocandins to azoles is recommended by several medical societies in Candida infections. We summarise the evidence of DES on clinical and microbiological cure and 30-day survival and compare it with continuing the treatment with echinocandins (non-DES). METHODS: We searched MEDLINE, Embase, Web of Science and Scopus. Studies describing DES in inpatients and reporting any of the outcomes evaluated were included. Pooled estimates of the tree outcomes were calculated with a fixed or random-effects model. Heterogeneity was explored stratifying by subgroups and via meta-regression. This systematic review is registered with PROSPERO (CRD42023475486). RESULTS: Of 1853 records identified, 9 studies were included, totalling 1575 patients. Five studies stepped-down to fluconazole; one to voriconazole and three to any of azoles. The mean day of DES was 5.2 (4.6-6.5) days. The clinical cure OR was 1.29 (95% CI: 0.88-1.88); the microbiological cure 1.62 (95% CI: 0.71-3.71); and 30-day survival 2.17 (95% CI: 1.09-4.32). The 30-day survival data into subgroups showed higher effect on critically ill patients and serious-risk bias studies. Meta-regression did not identify significant effect modifiers. CONCLUSIONS: DES is a safe strategy; it showed no higher 30-day mortality and a trend towards greater clinical and microbiological cure.

Insights into the anti-Candida albicans properties of natural phytochemicals: An in vitro and in vivo investigation.

Invasive candidiasis, attributed to Candida albicans, has long been a formidable threat to human health. Despite the advent of effective therapeutics in recent decades, the mortality rate in affected patient populations remains discouraging. This is exacerbated by the emergence of multidrug resistance, significantly limiting the utility of conventional antifungals. Consequently, researchers are compelled to continuously explore novel solutions. Natural phytochemicals present a potential adjunct to the existing arsenal of agents. Previous studies have substantiated the efficacy of phytochemicals against C. albicans. Emerging evidence also underscores the promising application of phytochemicals in the realm of antifungal treatment. This review systematically delineates the inhibitory activity of phytochemicals, both in monotherapy and combination therapy, against C. albicans in both in vivo and in vitro settings. Moreover, it elucidates the mechanisms underpinning the antifungal properties, encompassing (i) cell wall and plasma membrane damage, (ii) inhibition of efflux pumps, (iii) induction of mitochondrial dysfunction, and (iv) inhibition of virulence factors. Subsequently, the review introduces the substantial potential of nanotechnology and photodynamic technology in enhancing the bioavailability of phytochemicals. Lastly, it discusses current limitations and outlines future research priorities, emphasizing the need for high-quality research to comprehensively establish the clinical efficacy and safety of phytochemicals in treating fungal infections. This review aims to inspire further contemplation and recommendations for the effective integration of natural phytochemicals in the development of new medicines for patients afflicted with C. albicans.

Challenges in management of Candida auris meningitis secondary to infected ventriculoperitoneal shunt - A case report.

Meningitis in patients with ventriculo-peritoneal shunt (VP shunt) caused by various species of Candida have been widely described in literature. However, reports describing Candida auris as a cause of meningitis is limited. In this case report we describe a case of multidrug resistant Candida auris meningitis secondary to VP shunt infection successfully treated with intrathecal amphotericin B deoxycholate and intravenous liposomal amphotericin B. This is the second case report of successful treatment of Candida auris meningitis from India. More literature regarding the use of intrathecal/intraventricular echinocandins including optimal dosing and duration of therapy is needed.

Holotoxin A1 from Apostichopus japonicus inhibited oropharyngeal and intra-abdominal candidiasis by inducing oxidative damage in Candida albicans.

BACKGROUND AND PURPOSE: The holotoxin A1, isolated from Apostichopus japonicus, exhibits potent antifungal activities, but the mechanism and efficacy against candidiasis are unclear. In this study we have studied the antifungal effects and mechanism of holotoxin A1 against Candida albicans and in murine oropharyngeal and intra-abdominal candidiasis. EXPERIMENTAL APPROACH: The antifungal effect of holotoxin A1 against C. albicans was tested in vitro. To explore the antifungal mechanism of holotoxin A1, the transcriptome, ROS levels, and mitochondrial function of C. albicans was evaluated. Effectiveness and systematic toxicity of holotoxin A1 in vivo was assessed in the oropharyngeal and intra-abdominal candidiasis models in mice. KEY RESULTS: Holotoxin A1 was a potent fungicide against C. albicans SC5314, clinical strains and drug-resistant strains. Holotoxin A1 inhibited oxidative phosphorylation and induced oxidative damage by increasing intracellular accumulation of ROS in C. albicans. Holotoxin A1 induced dysfunction of mitochondria by depolarizing the mitochondrial membrane potential and reducing the production of ATP. Holotoxin A1 directly inhibited the enzymatic activity of mitochondrial complex I and antagonized with the rotenone, an inhibitor of complex I, against C. albicans. Meanwhile, the complex I subunit NDH51 null mutants showed a decreased susceptibility to holotoxin A1. Furthermore, holotoxin A1 significantly reduced fungal burden and infections with no significant systemic toxicity in oropharyngeal and intra-abdominal candidiasis in murine models. CONCLUSION AND IMPLICATIONS: Holotoxin A1 is a promising candidate for the development of novel antifungal agents against both oropharyngeal and intra-abdominal candidiasis, especially when caused by drug-resistant strains.

Isolated Cutaneous Granuloma Caused by Candida Parapsilosis: Case Report and Literature Review.

Candidal granuloma is an uncommon type of deep chronic cutaneous candidiasis. Candida albican is the most common causative pathogen for candidal granuloma. We report herein the original case of a 69-year-old Chinese woman presented with a 3-year of painful cutaneous lesion on the back of left hand. Physical examination revealed a 4 × 5 cm large infiltrative reddish plaque with unclear boundaries. The yellow-white crusts were observed on the uneven surface of plaque. Histopathological examination of biopsy tissue revealed that yeast cells and the horizontal section of hyphae in the dermis by hematoxylin eosin staining and periodic acid-Schiff staining. Finally, the pathogen was identified as Candida parapsilosis by mycological examination and molecular identification. The patient was treated with itraconazole oral 200 mg twice daily combined with topical terbinafine hydrochloride cream for 2 months. The lesions were fully resolved and no recurrence was observed. Since the cutaneous infection caused by C. parasilosis were rarely reported, we also reviewed all 11 cases of cutaneous infection caused by C. parapsilosis in the PubMed. Our study highlighted that chronic unilateral infiltrated plaques or ulcers should be aware of the occurrence of fungal granuloma including candidal granuloma especially in immunocompromised patients.

Mechanisms of antifungal resistance and developments in alternative strategies to combat Candida albicans infection.

Candida albicans is a commensal fungus that infects the humans and becomes an opportunistic pathogen particularly in immuno-compromised patients. Among the Candida genus, yeast C. albicans is the most frequently incriminated species and is responsible for nearly 50-90% of human candidiasis, with vulvovaginal candidiasis alone, affecting about 75% of the women worldwide. One of the significant virulence traits in C. albicans is its tendency to alternate between the yeast and hyphae morphotypes, accounting for the development of multi-drug resistance in them. Thus, a thorough comprehension of the decision points and genes controlling this transition is necessary, to understand the pathogenicity of this, naturally occurring, pernicious fungus. Additionally, the formation of C. albicans biofilm is yet another pathogenesis trait and a paramount cause of invasive candidiasis. Since 1980 and in 90 s, wide spread use of immune-suppressing therapies and over prescription of fluconazole, a drug used to treat chronic fungal infections, triggered the emergence of novel anti-fungal drug development. Thus, this review thoroughly elucidates the diseases associated with C. albicans infection as well as the anti-fungal resistance mechanism associated with them and identifies the emerging therapeutic agents, along with a rigorous discussion regarding the future strategies that can possibly be adopted for the cure of this deleterious pathogen.