The antifungals that are in current clinical practice have a high occurrence of a side effect and multidrug resistance (MDR). Researchers across the globe are trying to develop a suitable antifungal that has minimum side effect as well as no MDR issues. Due to serious undesired effects connected with individual antifungals, it is now necessary to introduce novel and effective drugs having numerous potentials to regulate complex therapeutic targets of several fungal infections simultaneously. Thus, by taking a lead from this subject, synthesis of potent antifungals from coumarin moiety could contribute to the development of promising antifungal. Its resemblance and structural diversity make it possible to produce an auspicious antifungal candidate. Due to the natural origin of coumarin, its presence in diversity, and their broad spectrum of pharmacological activities, it secures an important place for the researcher to investigate and develop it as a promising antifungal in future. This manuscript discusses the bioavailability of coumarin (natural secondary metabolic molecule) that has privileged scaffold for many mycologists to develop it as a broad-spectrum antifungal against several opportunistic mycoses. As a result, several different kinds of coumarin derivatives were synthesized and their antifungal properties were evaluated. This review compiles various coumarin derivatives broadly investigated for antifungal activities to understand its current status and future therapeutic scope in antifungal therapy.

Coumarins: antifungal effectiveness and future therapeutic scope

ABSTRACT It has previously been shown that overexpression of the CdMDR1 gene is a major contributor to resistance in fluconazole-resistant isolates of Candida dubliniensis. However, since CdMdr1p does not mediate transport of other azole drugs such as itraconazole, we investigated the molecular mechanisms of stable resistance to itraconazole obtained in three strains of C. dubliniensis (two with nonfunctional CdCDR1 genes and one with functional CdCDR1 genes) by serial exposure to this antifungal agent in vitro. Seven derivatives that were able to grow on agar medium containing 64 μg of itraconazole per ml were selected for detailed analysis. These derivatives were resistant to itraconazole, fluconazole, and ketoconazole but were not cross resistant to inhibitors. CdMDR1 expression was unchanged in the seven resistant derivatives and their parental isolates; however, all seven derivatives exhibited increased levels of CdERG11 expression, and six of the seven derivatives exhibited increased levels of CdCDR1 expression compared to the levels of expression by their respective parental isolates. Except for one derivative, the level of rhodamine 6G efflux was decreased in the itraconazole-resistant derivatives compared to the level of efflux in their parental isolates, suggesting altered membrane properties in these derivatives. Analysis of their membrane sterol contents was consistent with a defective sterol C5,6-desaturase enzyme (CdErg3p), which was confirmed by the identification of mutations in the alleles (CdERG3) encoding this enzyme and their lack of functional complementation in a Saccharomyces cerevisiae erg3 mutant. The results of this study show that the loss of function of CdErg3p was the primary mechanism of in vitro-generated itraconazole resistance in six of the seven the C. dubliniensis derivatives. However, the mechanism(s) of itraconazole resistance in the remaining seventh derivative has yet to be determined.

Investigation into the molecular mechanisms of itraconazole resistance in Candida dubliniensis

Fungal biofilms and drug resistance.

Tinea pedis, or athlete's foot, is common in elderly persons. It manifests as maceration in the interdigital web folds and as scaly plaques on the plantar surfaces of the feet. A potassium hydroxide evaluation can establish the diagnosis. Tinea pedis is commonly associated with xerosis. It is best treated with a topical antifungal agent; treatment can be aided by a keratolytic such as lactic acid 12% cream.

https://www.bmj.com/content/bmj/1/4977/1239.3.full.pdf

Athlete's Foot.

Invasive aspergillosis and scedosporiosis are life-threatening fungal infections with similar clinical manifestations in immunocompromised patients. Contrarily, Scedosporium apiospermum is susceptible to some azole derivative but often resistant to amphotericin B. Histopathological examination alone cannot diagnose these two fungal species. Pathogenesis studies could contribute to explore candidate protein markers for new diagnosis and treatment methods leading to a decrease in mortality. In the present study, proteomics was conducted to identify significantly altered proteins in A549 cells infected with or without Aspergillus fumigatus and S. apiospermum as measured at initial invasion. Protein validation was performed with immunogold labelling alongside immunohistochemical techniques in infected A549 cells and lungs from murine models. Further, cytokine production was measured, using the Bio-Plex-Multiplex immunoassay. The cytoskeletal proteins HSPA9, PA2G4, VAT1, PSMA2, PEX1, PTGES3, KRT1, KRT9, CLIP1 and CLEC20A were mainly changed during A. fumigatus infection, while the immunologically activated proteins WNT7A, GAPDH and ANXA2 were principally altered during S. apiospermum infection. These proteins are involved in fungal internalisation and structural destruction leading to pulmonary disorders. Interleukin (IL)-21, IL-1α, IL-22, IL-2, IL-8, IL-12, IL-17A, interferon-γ and tumour necrosis factor-α were upregulated in both aspergillosis and scedosporiosis, although more predominately in the latter, in accordance with chitin synthase-1 and matrix metalloproteinase levels. Our results demonstrated that during invasion, A. fumigatus primarily altered host cellular integrity, whereas S. apiospermum chiefly induced and extensively modulated host immune responses.

Cytoskeletal Alteration Is an Early Cellular Response in Pulmonary Epithelium Infected with Aspergillus fumigatus Rather than Scedosporium apiospermum

Fungal pathogens represent a leading cause of life-threatening infections in debilitated patients and exert a substantial toll on health care resources. A major development in the past few years, resulting from extremely rapid technological advances, has been the elucidation of the genome sequences of all of the major human fungal pathogens. Together with the development of transcriptomics and proteomics, fungal pathogen research has entered the so-called “omics” era. However, despite the remarkable acceleration in the understanding of many molecular mechanisms underlying phenomena such as drug resistance, fungal virulence, and pathogenesis, many key aspects of the host-fungal interactions are still not fully understood.

This current issue provides in-depth review articles drafted by international experts tackling different perspectives of the host-pathogen interplay. Their contributions offer insights into aspects related to fungal virulence and drug resistance of both established and emerging fungal pathogens, as well as models to study their pathogenicity.

The paper by G. P. Moran and colleagues explains why Candida albicans has evolved to become such a successful opportunistic pathogen, by comparative global gene expression analysis performed on C. albicans and its most closely related species C. dubliniensis.

The epidemiology of invasive fungal infections has evolved over the past twenty years. Yeasts other than C. albicans and moulds other than Aspergillus fumigatus have emerged as significant causes of invasive mycoses in severely immunocompromised patients. Tools allowing a prompt diagnosis for these emerging pathogenic fungi are lacking, often leading to a delay in effective treatment and high mortality rates. This is the case for invasive mucormycosis, a rapidly progressing infection often refractory to antifungal therapy, with a negative prognosis in individuals with impaired immune defence. The key role of iron uptake, angioinvasion, and neurotropism in the virulence repertoire of this fascinating group of fungi is reviewed by G. Morace and E. Borghi.

Chitin is one of the most abundant biopolymers in nature and comprises part of the fungal cell wall structure. Although humans do not biosynthesize chitin, they do express chitin degrading enzymes. The targeted recognition of fungal chitin by the host may have implications for diagnostic assays, as well as for potential new therapeutic approaches. This emerging topic is reviewed by K. Vega and M. Kalkum. Another major process that influences fungal cell wall structure is protein glycosylation, which is essential for eukaryotic cells. However, the mechanisms by which carbohydrates play a role in the development of fungal diseases are still poorly characterised. In this context, C. Jin provides an overview on the contribution of protein glycosylation to growth, cell wall synthesis and development in A. fumigatus, possibly providing a novel strategy for drug development.

Histoplasma capsulatum is a major fungal pathogen endemic to the Americas, exhibiting a broad variety of clinical presentations, ranging from mild lung infection to life-threatening systemic infections. The severity of infection and its outcome result from a complex interaction between the virulence repertoire of the pathogen and the host's immune defences. The paper by M. R. Mihu and J. D. Nosanchuk focuses on the dynamic host-pathogen interplay in the context of the virulence arsenal displayed by the fungus and the innate and adaptive immune responses of the host.

The molecular mechanisms underlying the ability of dermatophytes to establish infection and persist in the host are reviewed by R. R. Achterman and T. C. White. Despite the fact that this group of filamentous fungi are the most common cause of cutaneous mycoses, very little is known about dermatophyte pathogenesis. The paper presents the current research status on dermatophyte virulence factors.

The ability of fungal cells to chemically communicate with each other and with other microorganisms has only recently been discovered. The paper by F. Cottier and F. A. Muhlschlegel depicts a fascinating picture of a closely connected microbial community in the environment, where multispecies communication takes place. Versatile fungal communicative competences are thought to have a significant impact on several fungal biological functions such as mating, growth, or the regulation of virulence factor expression. Among the latter, hyphal formation has been widely recognised to significantly contribute to the pathogenesis of several fungal species, by promoting adhesion to biotic or abiotic surfaces and tissue penetration. The paper by A. Brand presents the current knowledge on C. albicans hyphal growth during infection, addressing the issue of specific functions and mechanical/structural properties conferred by hyphal formation during infection.

Fungal pathogens have evolved complex mechanisms of resistance to antifungal drugs. The nature, frequency, and molecular mechanisms of resistance to currently used antifungals are the focus of the review by P. Vandeputte and colleagues, who also describe the latest approaches to develop new antifungal strategies.

A growing number of fungal pathogens have been associated with life-threatening infections resulting from biofilm-related infections that are particularly difficult to treat. Indeed, biofilm-embedded fungal cells are far more resistant to antifungal agents than their corresponding planktonic cells. The molecular basis of this remarkable resistance to antifungals has yet to be fully elucidated. In this respect, G. Ramage and coworkers review the latest findings on this topic and shed new light on the multifactorial nature of biofilm antifungal resistance. From a different perspective, H. Tournu and P. Van Dijck describe some of the most recent approaches shown to eradicate Candida biofilms, based on novel strategies to evaluate biofilm formation in vitro and in vivo.

The choice of the most appropriate experimental infection model to use for fungal pathogenesis-, virulence-, immunology-, and therapy-based studies is critical. In this issue, several contributions were made towards this topic. Mucosal and systemic models of Candida infection and virulence are discussed in depth by D. M. MacCallum, while the range of experimental models currently available for cryptococcosis is reviewed by W. Sabiiti and coworkers. G. Hamilos and colleagues offer a critical analysis of the use of Drosophila melanogaster as a surrogate model to study the immunopathogenesis of fungal infection and illustrate the recent advances in the study of medically important filamentous fungi in Drosophila.

Bioluminescent imaging is a powerful tool to perform real time evaluation of temporal and spatial progression of infections. Mainly used for the study of bacterial infection process, M. Brock discusses the application of bioluminescent imaging to the study of mycoses, summarising the key features of different luciferase systems and providing suggestions for future applications.

We believe that the collection of reviews authored by experts in the field presented here will provide a timely update of recent rapid developments in the field of medical mycology. We hope that the reviews will be helpful in assembling the interlocking pieces of the complex jigsaw that is the fungal-host interplay, as well as provide a basis for the generation of novel ideas and hypotheses for future experimentation.


Arianna Tavanti

Julian R. Naglik

Nir Osherov

/pdf/host-fungal-interactions-pathogenicity-versus-immunity-4mzanctoxj.pdf

Host-Fungal Interactions: Pathogenicity versus Immunity

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Host-Fungal Interactions: Pathogenicity versus Immunity