Mycobiome and Inflammatory Bowel Disease: Role in Disease Pathogenesis, Current Approaches and Novel Nutritional-based Therapies.

Inflammatory bowel disease (IBD), a disorder characterized by chronic inflammation of the gastrointestinal (GI) tract and a range of adverse health effects including diarrhea, abdominal pain, vomiting, and bloody stools, affects nearly 3.1 million genetically susceptible adults in the United States today. Although the etiology of IBD remains unclear, genetics, stress, diet, and gut microbiota dysbiosis- especially in immunocompromised individuals- have been identified as possible causes of disease. Although previous research has largely focused on the role of bacteria in IBD pathogenesis, recently observed alterations of fungal load and biodiversity in the GI tract of afflicted individuals suggest interkingdom interactions amongst different gut microbial communities, particularly between bacteria and fungi. These discoveries point to the potential utilization of treatment approaches such as antibiotics, antifungals, probiotics, and postbiotics that target both bacteria and fungi in managing IBD. In this review, we discuss the impact of specific fungi on disease pathogenesis, with a focus on the highly virulent genus Candida and how the presence of certain co-enzymes impacts its virulence. In addition, we evaluate current gut microbiome-based therapeutic approaches with the intention of better understanding the mechanisms behind novel therapies.

Recently observed alterations of fungal load in the gastrointestinal tract of IBD patients suggest interkingdom interactions amongst different gut microbial communities. These discoveries point to the potential utilization of antifungals and probiotics that target bacteria and fungi in managing IBD.

A Microbiome-Driven Approach to Combating Depression During the COVID-19 Pandemic.

The significant stressors brought about and exacerbated by COVID-19 are associated with startling surges in mental health illnesses, specifically those related to depressive disorders. Given the huge impact of depression on society, and an incomplete understanding of impactful therapeutics, we have examined the current literature surrounding the microbiome and gut-brain axis to advance a potential complementary approach to address depression and depressive disorders that have increased during the COVID-19 pandemic. While we understand that the impact of the human gut microbiome on emotional health is a newly emerging field and more research needs to be conducted, the current evidence is extremely promising and suggests at least part of the answer to understanding depression in more depth may lie within the microbiome. As a result of these findings, we propose that a microbiome-based holistic approach, which involves carefully annotating the microbiome and potential modification through diet, probiotics, and lifestyle changes, may address depression. This paper's primary purpose is to shed light on the link between the gut microbiome and depression, including the gut-brain axis and propose a holistic approach to microbiome modification, with the ultimate goal of assisting individuals to manage their battle with depression through diet, probiotics, and lifestyle changes, in addition to offering a semblance of hope during these challenging times.

Efficacy of Voriconazole, Isavuconazole, Fluconazole, and Anidulafungin in the Treatment of Emerging Candida auris Using an Immunocompromised Murine Model of Disseminated Candidiasis.

Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo. MICs for anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 µg/ml, respectively. Significant in vivo efficacy was observed in the anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to that in the untreated group (P values of <0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacies against C. auris, whereas isavuconazole did not show significant in vivo activity.

Outcomes by MIC Values for Patients Treated with Isavuconazole or Voriconazole for Invasive Aspergillosis in the Phase 3 SECURE and VITAL Trials.

This pooled analysis evaluated the relationship of isavuconazole and voriconazole MICs of Aspergillus pathogens at baseline with all-cause mortality and clinical outcomes following treatment with either drug in the SECURE and VITAL trials. Isavuconazole and voriconazole may have had reduced efficacy against pathogens with drug MICs of ≥16 µg/ml, but there was no relationship with clinical outcomes in cases where the MIC was <16 µg/ml for either drug.

Examining the Benefits of the Boron-Based Mechanism of Action and Physicochemical Properties of Tavaborole in the Treatment of Onychomycosis.

Onychomycosis is a fungal infection of the nail primarily caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The topical-based treatment of onychomycosis remains a challenge because of the difficulty associated with penetrating the dense, protective structure of the keratinized nail plate. Tavaborole is a novel small-molecule antifungal agent recently approved in the United States for the topical treatment of toenail onychomycosis. The low molecular weight, slight water solubility, and boron chemistry of tavaborole maximize nail penetration after topical application, allowing for effective targeting of the infection in the nail bed. The efficacy of tavaborole is associated with its novel mechanism of action, whereby it inhibits the fungal leucyl-tRNA synthetase (LeuRS) enzyme. Because LeuRS is an essential component in fungal protein synthesis, inhibition of LeuRS ultimately leads to fungal cell death. Tavaborole is the first boron-based antifungal medication approved for the treatment of mild-to-moderate onychomycosis and presents patients with a new topical option. Previously, ciclopirox and efinaconazole were the only approved topical treatments for onychomycosis. This article details the properties that are at the core of the clinical benefits associated with tavaborole.

The Role of Echinocandins in Candida Biofilm-Related Vascular Catheter Infections: In Vitro and In Vivo Model Systems.

Candida biofilm-associated infections of central venous catheters are a challenging therapeutic problem. Recent in vitro and in vivo studies of the structure, formation, pathogenesis, and treatment establish a rationale for new approaches to management of these tenacious infections.

Potentiation of azole antifungals by 2-adamantanamine.

Azoles are among the most successful classes of antifungals. They act by inhibiting α-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics.

Iron deprivation induces EFG1-mediated hyphal development in Candida albicans without affecting biofilm formation.

In this study, we investigated the role of cellular iron status in hyphae and biofilm formation in Candida albicans. Iron deprivation by a chelator, bathophenanthrolene disulfonic acid, promoted hyphal development even in nonhyphal-inducing media without affecting growth of C. albicans cells. Iron-acquisition defective mutants, Deltaftr1 and Deltaccc2, also showed hyphal formation, which was prevented by iron supplementation. Notably, most of the tested morphological mutants Deltacph1, Deltaefh1 and Deltatpk1 continued to form hyphae under iron-deprived conditions, except the Deltaefg1 null mutant, which showed a complete block in hyphae formation. The role of EFG1 in filamentation under iron-deprived conditions was further confirmed by Northern analysis, which showed a considerable upregulation of the EFG1 transcript. Of notable importance, all the morphological mutants including Deltaefg1 mutant possessed enhanced membrane fluidity under iron-deprived conditions; however, this did not appear to contribute to hyphal development. Interestingly, iron deprivation did not affect the ability of C. albicans to form biofilms on the catheter surface and led to no gross defects in azole resistance phenotype of these biofilms of C. albicans cells. Our study, for the first time, establishes a link between cellular iron, Efg1p and hyphal development of C. albicans cells that is independent of biofilm formation.

Combination treatment of invasive fungal infections.

The persistence of high morbidity and mortality from systemic fungal infections despite the availability of novel antifungals points to the need for effective treatment strategies. Treatment of invasive fungal infections is often hampered by drug toxicity, tolerability, and specificity issues, and added complications often arise due to the lack of diagnostic tests and to treatment complexities. Combination therapy has been suggested as a possible approach to improve treatment outcome. In this article, we undertake a historical review of studies of combination therapy and also focus on recent studies involving newly approved antifungal agents. The limitations surrounding antifungal combinations include nonuniform interpretation criteria, inability to predict the likelihood of clinical success, strain variability, and variations in pharmacodynamic/pharmacokinetic properties of antifungals used in combination. The issue of antagonism between polyenes and azoles is beginning to be addressed, but data regarding other drug combinations are not adequate for us to draw definite conclusions. However, recent data have identified potentially useful combinations. Standardization of assay methods and adoption of common interpretive criteria are essential to avoid discrepancies between different in vitro studies. Larger clinical trials are needed to assess whether combination therapy improves survival and treatment outcome in the most seriously debilitated patients afflicted with life-threatening fungal infections.

Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B.

Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis.