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Chloroquine (CQ) has been a good treatment for antimalarial mainstay for several decades; additionally discovered, it has a significant therapeutic impact on some instances of fungal inhibition. This study focused on the effect of novel CQ compounds on the activity of two different species of fungi, Aspergillus niger and Aspergillus falves. The activity of each CQ derivative was monitored using Nuclear magnetic resonance spectroscopy (NMR), minimal inhibitory concentration and physical parameters such as optical microscopy, UV/visible absorbance and optical band gap. NMR indicated the conjugation between the substrate and amino acid. The optical microscopic images indicated homogeneously distributed and uniform density distribution of CQ-derivative particles on the glass substrates. The samples' presented absorption peaks at 203, 207 and 220 nm wavelengths, suggesting the important electronic transition with reducing the indirect bandgap from 4.1 eV to 3.95 eV. These compounds have the best antifungal growth inhibitory properties and excellent features, indicating cosmetics use. [ABSTRACT FROM AUTHOR]

Candida albicans is one of the agents of invasive candidiasis, a life-threatening disease strongly associated with hospitalization, particularly among patients in intensive care units with central venous catheters. This study aimed to evaluate the synergistic activity of the antifungal peptide ToAP2 combined with fluconazole against C. albicans biofilms grown on various materials. We tested combinations of different concentrations of the peptide ToAP2 with fluconazole on C. albicans biofilms. These biofilms were generated on 96-well plates, intravenous catheters, and infusion tubes in RPMI medium at two maturation stages. Scanning electron microscopy and atomic force microscopy were employed to assess the biofilm structure. We also evaluated the expression of genes previously proven to be involved in C. albicans biofilm formation in planktonic and biofilm cells after treatment with the peptide ToAP2 using qPCR. ToAP2 demonstrated a synergistic effect with fluconazole at concentrations up to 25 µM during both the early and mature stages of biofilm formation in 96-well plates and on medical devices. Combinations of 50, 25, and 12.5 µM of ToAP2 with 52 µM of fluconazole significantly reduced the biofilm viability compared to individual treatments and untreated controls. These results were supported by substantial structural changes in the biofilms observed through both scanning and atomic force microscopy. The gene expression analysis of C. albicans cells treated with 25 µM of ToAP2 revealed a decrease in the expression of genes associated with membrane synthesis, along with an increase in the expression of genes involved in efflux pumps, adhesins, and filamentation. Our results highlight the efficacy of the combined ToAP2 and fluconazole treatment against C. albicans biofilms. This combination not only shows therapeutic potential but also suggests its utility in developing preventive biofilm tools for intravenous catheters. [ABSTRACT FROM AUTHOR]

Background: The increasing prevalence of fungal infections necessitates broader use of antifungal medications. However, the prevalence of adverse drug events (ADEs) restricts their clinical application. This study aimed to develop a reliable ADEs trigger for antifungals to enable proactive ADEs monitoring, serving as a reference for ADEs prevention and control. Methods: This investigation comprises two phases. Initially, the trigger was established via a literature review, extraction of relevant items, and refinement through Delphi expert consultation. Subsequently, the validity of the trigger was assessed by analyzing hospital records of antifungal drug users from 1 January 2019 to 31 December 2020. The correlation between each trigger signal and ADEs occurrence was examined, and the sensitivity and specificity of the trigger were evaluated through the spontaneous reporting system (SRS) and Global Trigger Tool (GTT). Additionally, risk factors contributing to adverse drug events (ADEs) resulting from antifungal use were analyzed. Results: Twenty-one preliminary triggers were refined into 21 final triggers after one expert round. In the retrospective analysis, the positive trigger rate was 65.83%, with a positive predictive value (PPV) of 28.75%. The incidence of ADEs in inpatients was 28.75%, equating to 44.58 ADEs per 100 admissions and 33.04 ADEs per 1,000 patient days. Predominant ADEs categories included metabolic disturbances, gastrointestinal damage, and skin rashes. ADEs severity was classified into 36 cases at grade 1, 160 at grade 2, and 18 at grade 3. The likelihood of ADEs increased with longer stays, more positive triggers, and greater comorbidity counts. Conclusion: This study underscores the effectiveness of the GTT in enhancing ADEs detection during antifungal medication use, thereby confirming its value as a monitoring tool. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is at the top of the list of "most wanted" human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans, mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1, ERG11, and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans, with genome plasticity as the accomplice. [ABSTRACT FROM AUTHOR]

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Two microorganisms Staphylococcus aureusandCandida albicansisolated from a mixed bacterial-fungal biofilm of horse wound were studied. Resistance profile of these clinical strains to antimicrobial agents was determined using standard disc diffusion method on solid nutrient medium in the laboratory. Next, Farnesol was added to the disks at concentrations of 12.5200M/ml (experiment) or physiologic saline solution (control). The experiments showed that in most cases addition of Farnesol increased sensitivity of microorganisms to antimicrobial drugs, and there were no cases of a negative effect of Farnesol on sensitivity. Moreover, the best results of synergism were observed in combination with antifungal drugs rather than with antibacterial drugs. There were also unique indicators: sensitivity ofC. albicansto Nystatin and Miconazole doubled after the addition of Farnesol at a concentration of 25200 M/ml. Furthermore, it was proved that the clinical strain ofS. aureuswas completely resistant to penicillin. And sensitivity appeared after the addition of Farnesol. A similar situation was with theCandidastrain: resistance to Amphotericin B was initially observed, and in combination with Farnesol, this drug began to work even in small concentrations.In vivodata indicate that Farnesol has an adjuvant effect in combination with most antibiotics and/or antifungal drugs.

Superficial cutaneous mycoses are a challenge for practical healthcare all over the world. Considering high incidence of cutaneous mycoses, it is obvious that there is a need to monitor the efficacy and safety of topical antifungals confirmed in the large-scale clinical trials. Today, drugs of two classes, allylamines and azoles, are considered to be the most effective antifungals for treatment of cutaneous mycoses. The review provides the analysis of the results of large-scale clinical trials and meta-analyses aimed to determine the role of modern topical antifungals in treatment of cutaneous mycoses. The options for optimization of the cutaneous mycosis treatment are exemplified by naftifine as a founder of the class of allylamines possessing not only antifungal, but also antibacterial and anti-inflammatory activity.

Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen Candida auris. In this study, the most cost-effective drug repurposing technology was adopted to identify an appropriate option among the 1615 clinically approved drugs with anti-C. auris activity. High-throughput virtual screening of 1,3-beta-glucanosyltransferase inhibitors was conducted, followed by an analysis of the stability of 1,3-beta-glucanosyltransferase drug complexes and 1,3-beta-glucanosyltransferase–dutasteride metabolite interactions and the confirmation of their activity in biofilm formation and planktonic growth. The analysis identified dutasteride, a drug with no prior antifungal indications, as a potential medication for anti-auris activity in seven clinical C. auris isolates from Saudi Arabian patients. Dutasteride was effective at inhibiting biofilm formation by C. auris while also causing a significant reduction in planktonic growth. Dutasteride treatment resulted in disruption of the cell membrane, the lysis of cells, and crushed surfaces on C. auris, and significant (p-value = 0.0057) shrinkage in the length of C. auris was noted at 100,000×. In conclusion, the use of repurposed dutasteride with anti-C. auris potential can enable rapid recovery in patients with difficult-to-treat candidiasis caused by C. auris and reduce the transmission of nosocomial infection. [ABSTRACT FROM AUTHOR]

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented. [ABSTRACT FROM AUTHOR]

Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules. [ABSTRACT FROM AUTHOR]

Infection caused by the Humicola sp is extremely rare. We report the first case of fungal keratitis caused by Humicola pulvericola (H. pulvericola) in a 63-year-old man with a history of exposed to hot oil two weeks ago who developed keratitis. Direct examination of confocal microscopy and corneal scrapings showed fungal hyphae and isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. The in vitro antifungal susceptibilities of the case strain were tested for five antifungal agents. The results showed that the infectious agent was resistant towards fluconazole, caspofungin and amphotericin B; itraconazole and voriconazole were highly effective against H. pulvericola. He was diagnosed with H. pulvericola keratitis and treated with oral itraconazole and natamycin eyedrops. After one month of treatment, the lesion gradually improved, with the best-corrected visual acuity improving to 0.8. [ABSTRACT FROM AUTHOR]

Physicians are increasingly prescribing antifungal drugs empirically to treat hospital-acquired infections quickly. This makes it obvious that fungal infections require more attention and systematic monitoring of resistance among them. The aim of the study was to identify antifungal drugs that retain their efficacy against C. albicans isolates. There were 17 clinical isolates of Candida albicans obtained from patients and tested for susceptibility to antifungal drugs using the standard double dilution method. Amphotericin B, fluconazole, itraconazole, micafungin, and posaconazole were used in the study. To determine the groups of antimycotics to which the studied microorganisms retain sensitivity, a hierarchical cluster analysis was performed using the Ward's method. The tested representatives of the genus Candida showed the lowest sensitivity to fluconazole. The efficacy of amphotericin B and itraconazole was almost at the same level. In turn, micafungin and posaconazole showed the best results against C. albicans isolates. Ward's cluster analysis combined the results of C. albicans susceptibility to fluconazole, micafungin and itraconazole by the highest mathematical similarity. Amphotericin B and posaconazole were combined into one cluster due to their better efficacy against Candida albicans isolates.

This document is an editorial published in the journal Frontiers in Fungal Biology. It discusses the importance of studying fungal biology, particularly in relation to pathogenesis in humans. The World Health Organization has identified 19 fungal pathogens of critical, high, or medium priority, highlighting the need for research and interventions to address fungal infections and antifungal resistance. The editorial also mentions specific studies included in the research topic, such as the investigation of fungal-host interactions and the development of new study models like cell cultures and organoids. Overall, the document emphasizes the recent advances in understanding fungal pathogen biology and the importance of exploring new therapeutic strategies. [Extracted from the article]

Abstract Candida albicans is resistant to various antifungal drugs, this presents a significant problem on a global scale. This study investigates a novel approach on the potential fungicidal effects of α-Phellandrene combinations with fluconazole and amphotericin B against antibiotic resistant C. albicans. The agar well diffusion experiment was used to measure the anti-candida activity of α-Phellandrene which exhibited a zone of inhibition of 24 ± 0.5 mm and 22 ± 0.5 mm against the C. albicans cells (MTCC277 and ATCC90028), respectively. Additionally, the fungicidal minimum inhibitory concentration (MIC) ranged 0.0312–0.0156 mg/ml (w/v) against C. albicans strains. It was determined to have powerful and efficient antifungal action against Candida cells. Further, the synergistic potential was evaluated by employing a time kill assay and a checkerboard technique, respectively, which revealed after 16 h, the colony count of C. albicans cells ATCC90028 (2.56 ± 0.33) and MTCC277 (2.53 ± 0.33) dropped by a log10 when treated with a combination of α-Phellandrene and Fluconazole and α-Phellandrene and amphotericin B exhibited synergy against both C. albicans strains ATCC90028 and MTCC277 (2.42 ± 0.28 and 2.00 ± 0.21) log10 reduction in colony count, respectively, Additionally, 16–624-fold increase in the antifungal efficacy of clinical medicines, with total cell death occurring after 16 h. α-Phellandrene and antifungal drugs were tested in combination with the osmoprotectant test, ergosterol test and FESEM observations to determine their modes of action. In the era of multidrug-resistant diseases antibiotic resistance can be curtailed in its tracks with the help of combination treatments that allow for lower drug doses.

Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is themost prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCRbased tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs. [ABSTRACT FROM AUTHOR]

Historically, fungi were mainly identified as plant and insect pathogens since they grow at 28°C. At the same time, bacteria are known to be the most common human pathogens as they are compatible with the host body temperature of 37°C. Because of immunocompromised hosts, cancer therapy, and malnutrition, fungi are rapidly gaining attention as human pathogens. Over 150 million people have severe fungal infections, which lead to approximatelymore than one million deaths per year. Moreover, diseases like cancer involving long-term therapy and prophylactic use of antifungal drugs in high-risk patients have increased the emergence of drug-resistant fungi, including highly virulent strains such as Candida auris. This clinical spectrum of fungal diseases ranges from superficial mucocutaneous lesions tomore severe and life-threatening infections. This review article summarizes the effect of hospital environments, especially during the COVID-19 pandemic, on fungal infections and emerging pathogens. The review also provides insights into the various antifungal drugs and their existing challenges, thereby driving the need to search for novel antifungal agents. [ABSTRACT FROM AUTHOR]

Fungal infections represent a serious global health threat. The new emerging pathogens and the spread of different forms of resistance are now hardly challenging the tools available in therapy and diagnostics. With the commonly used diagnoses, fungal identification is often slow and inaccurate, and, on the other hand, some drugs currently used as treatments are significantly affected by the decrease in susceptibility. Herein, the antifungal arsenal is critically summarized. Besides describing the old approaches and their mechanisms, advantages, and limitations, the focus is dedicated to innovative strategies which are designed, identified, and developed to take advantage of the discrepancies between fungal and host cells. Relevant pathways and their role in survival and virulence are discussed as their suitability as sources of antifungal targets. In a similar way, molecules with antifungal activity are reported as potential agents/precursors of the next generation of antimycotics. Particular attention was devoted to biotechnological entities, to their novelty and reliability, to drug repurposing and restoration, and to combinatorial applications yielding significant improvements in efficacy. Key points: • New antifungal agents and targets are needed to limit fungal morbidity and mortality. • Therapeutics and diagnostics suffer of delays in innovation and lack of targets. • Biologics, drug repurposing and combinations are the future of antifungal treatments. [ABSTRACT FROM AUTHOR]

Lung transplantation is a viable option for end-stage lung diseases. However, it comes with numerous complications that may lead to various morbidities due to surgical procedures, rejections, and medical treatments. Fungal infection is a common complication of immunsupressive treatment. On the fifteenth postoperative day, bronchoscopy of a female recipient, who had undergone bilateral sequential lung transplantation for bronchiectasis, revealed an appearance consistent with aspergillus pseudomembranes around the left bronchial anastomosis. After microbiologically confirming the diagnosis, systemic voriconazole treatment was initiated. The recipient made it through the first three months of treatment without complications. However, since the membranes did not fully resolved, the decision was made to extend the treatment. From the fourth month of treatment, the recipient began experiencing generalized pain. Subsequent examinations revealed diffuse periostitis in the bones. After consultations and evaluations with relevant departments, other differential diagnoses were ruled out, leading to a diagnosis of voriconazole-induced periostitis. This diagnosis was further confirmed when symptoms improved three days after discontinuing the drug. Clinicians should be alert to this potential complication and correlate it with the clinical history of solid organ transplantation to avoid unnecessary investigations. [ABSTRACT FROM AUTHOR]

Invasive candidiasis caused by the pathogenic Candida yeast species has resulted in elevating global mortality. The pathogenicity of Candida spp. is not only originated from its primary invasive yeast-to-hyphal transition; virulence factors (transcription factors, adhesins, invasins, and enzymes), biofilm, antifungal drug resistance, stress tolerance, and metabolic adaptation have also contributed to a greater clinical burden. However, the current research theme in fungal pathogenicity could hardly be delineated with the increasing research output. Therefore, our study analysed the research trends in Candida pathogenesis over the past 37 years via a bibliometric approach against the Scopus and Web of Science databases. Based on the 3993 unique documents retrieved, significant international collaborations among researchers were observed, especially between Germany (Bernhard Hube) and the UK (Julian Naglik), whose focuses are on Candida proteinases, adhesins, and candidalysin. The prominent researchers (Neils Gow, Alistair Brown, and Frank Odds) at the University of Exeter and the University of Aberdeen (second top performing affiliation) UK contribute significantly to the mechanisms of Candida adaptation, tolerance, and stress response. However, the science mapping of co-citation analysis performed herein could not identify a hub representative of subsequent work since the clusters were semi-redundant. The co-word analysis that was otherwise adopted, revealed three research clusters; the cluster-based thematic analyses indicated the severeness of Candida biofilm and antifungal resistance as well as the elevating trend on molecular mechanism elucidation for drug screening and repurposing. Importantly, the in vivo pathogen adaptation and interactions with hosts are crucial for potential vaccine development. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important class of anti-inflammatory drugs widely used for the treatment of musculoskeletal disorders, mild-to-moderate pain, and fever. This review aimed to explain the functional role and possible mechanisms of the antifungal effects of NSAIDs alone or in combination with antifungal drugs in vitro and in vivo. Several studies reported that NSAIDs such as aspirin, ibuprofen, diclofenac, indomethacin, ketorolac, celecoxib, flurbiprofen, and nimesulide had antifungal activities in vitro, either fungistatic or fungicidal, against different strains of Candida, Aspergillus, Cryptococcus, Microsporum, and Trichophyton species. These drugs inhibited biofilm adhesion and development, and yeast-to-hypha conversion which may be related to a prostaglandin E2 (PGE2)/PGEx-dependent mechanism. Modulating PGE2 levels by NSAIDs during fungal infection can be introduced as a possible mechanism to overcome. In addition, some important mechanisms of the antifungal activities of NSAIDs and their new derivatives on fungi and host immune responses are summarized. Overall, we believe that using NSAIDs along with classical antifungal drugs has the potential to be investigated as a novel therapeutic strategy in clinical studies. Furthermore, combination therapy can help manage resistant strains, increase the efficacy of antifungal drugs, and reduce toxicity. [ABSTRACT FROM AUTHOR]

Candida albicans is one of the agents of invasive candidiasis, a life-threatening disease strongly associated with hospitalization, particularly among patients in intensive care units with central venous catheters. This study aimed to evaluate the synergistic activity of the antifungal peptide ToAP2 combined with fluconazole against C. albicans biofilms grown on various materials. We tested combinations of different concentrations of the peptide ToAP2 with fluconazole on C. albicans biofilms. These biofilms were generated on 96-well plates, intravenous catheters, and infusion tubes in RPMI medium at two maturation stages. Scanning electron microscopy and atomic force microscopy were employed to assess the biofilm structure. We also evaluated the expression of genes previously proven to be involved in C. albicans biofilm formation in planktonic and biofilm cells after treatment with the peptide ToAP2 using qPCR. ToAP2 demonstrated a synergistic effect with fluconazole at concentrations up to 25 µM during both the early and mature stages of biofilm formation in 96-well plates and on medical devices. Combinations of 50, 25, and 12.5 µM of ToAP2 with 52 µM of fluconazole significantly reduced the biofilm viability compared to individual treatments and untreated controls. These results were supported by substantial structural changes in the biofilms observed through both scanning and atomic force microscopy. The gene expression analysis of C. albicans cells treated with 25 µM of ToAP2 revealed a decrease in the expression of genes associated with membrane synthesis, along with an increase in the expression of genes involved in efflux pumps, adhesins, and filamentation. Our results highlight the efficacy of the combined ToAP2 and fluconazole treatment against C. albicans biofilms. This combination not only shows therapeutic potential but also suggests its utility in developing preventive biofilm tools for intravenous catheters.

Carbon nanotubes (CNTs) have emerged as the brightest nascent artifact to deliver antifungal drugs in drug delivery applications, health care, and pharmaceutical industries. Excellent physio‐chemical features such as huge surface area, tunable side wall, and microneedle‐like morphology make CNTs suitable for drug carriers. Chemical attachments (covalent and non‐covalent functionalization) result in the formation of functionalized CNTs (F‐CNTs) and CNT‐based hybrid materials (CNT‐HMs). These F‐CNTs and CNT‐HMs have substantial antifungal activity and also have the potential to immobilize antifungal drugs such as amphotericin B, nystatin, curcumin, etc. on the exterior or interior surface, securely transport to the target sites, permeate through bio‐barriers, and release these drugs in a controlled manner. As antifungal drug carriers, F‐CNT and CNT‐HMs exhibit more excellent antifungal activity than other conventional drug delivery systems and have the potency to invade biofilm to circumvent the multidrug resistance of fungal species. This review focuses on CNTs and CNT‐HMs for antifungal drug delivery, including their functionalization methods, drug loading approaches, drug release mechanism, cellular internalization, delivery efficiency, and cellular toxicities with their workaround. [ABSTRACT FROM AUTHOR]

The increasing cases of drug resistance and high toxicity associated with the currently used antifungal agents are a worldwide public health concern. There is an urgent need to develop new antifungal drugs with unique target mechanisms. Plant-based compounds, such as carvacrol, eugenol, coumarin, cinnamaldehyde, curcumin, thymol, etc., have been explored for the development of promising antifungal agents due to their diverse biological activities, lack of toxicity, and availability. However, researchers around the world are unable to fully utilize the potential of natural products due to limitations, such as their poor bioavailability and aqueous solubility. The development of hybrid molecules containing natural products is a promising synthetic approach to overcome these limitations and control microbes' capability to develop resistance. Based on the potential advantages of hybrid compounds containing natural products to improve antifungal activity, there have been different reported synthesized hybrid compounds. This paper reviews different literature to report the potential antifungal activities of hybrid compounds containing natural products. [ABSTRACT FROM AUTHOR]

The chemical structure of a drug is considered as a chemical graph G=V,E, where the vertex set V is the set of atoms and the edge set E is the set of bonds between the atoms. Fungi‐related diseases are becoming a more serious medical problem as a result of changes in the worldwide environment. In this article, the QSPR analysis is performed to predict the ADMET properties of the drugs used to treat fungal infections such as mucormycosis, blastomycosis, invasive candidiasis, talaromycosis, cryptococcus, neoformans, and so forth. The antifungal drugs posaconazole, isavuconazole, and amphotericin B and its analogs are considered to carry out the QSPR analysis. The domination numbers of these drugs are determined to correlate with their ADMET properties through cubic regression and the analysis suggests a high association between the domination numbers of drugs and their ADMET properties. The ADMET properties of the analog structures of the drug amphotericin B are also predicted in this QSPR analysis. [ABSTRACT FROM AUTHOR]

Understanding the metabolism of pharmaceutical compounds is a fundamental prerequisite for ensuring their safety and efficacy in clinical use. However, conventional methods for monitoring drug metabolism often come with the drawbacks of being time-consuming and costly. In an ongoing quest for innovative approaches, the application of electrochemistry in metabolism studies has gained prominence as a promising approach for the synthesis and analysis of drug transformation products. In this study, we investigated the hepatic metabolism of voriconazole, an antifungal medication, by utilizing human liver microsomes (HLM) assay coupled with LC-MS. Based on the obtained results, the electrochemical parameters were optimized to simulate the biotransformation reactions. Among the various electrodes tested, the chemometric analysis revealed that the iron(II) phthalocyanine electrode was the most effective in catalyzing the formation of all hepatic voriconazole metabolites. These findings exemplify the potential of phthalocyanine electrodes as an efficient and cost-effective tool for simulating the intricate metabolic processes involved in drug biotransformation, offering new possibilities in the field of pharmaceutical research. Additionally, in silico analysis showed that two detected metabolites may exhibit significantly higher acute toxicity and mutagenic potential than the parent compound. [ABSTRACT FROM AUTHOR]

Due to the increasing prevalence of fungal diseases caused by fungi of the genus Candida and the development of pathogen resistance to available drugs, the need to find new effective antifungal agents has increased. Azole antifungals, which are inhibitors of sterol-14α-demethylase or CYP51, have been widely used in the treatment of fungal infections over the past two decades. Of special interest is the study of C. krusei CYP51, since this fungus exhibit resistance not only to azoles, but also to other antifungal drugs and there is no available information about the ligand-binding properties of CYP51 of this pathogen. We expressed recombinant C. krusei CYP51 in E. coli cells and obtained a highly purified protein. Application of the method of spectrophotometric titration allowed us to study the interaction of C. krusei CYP51 with various ligands. In the present work, the interaction of C. krusei CYP51 with azole inhibitors, and natural and synthesized steroid derivatives was evaluated. The obtained data indicate that the resistance of C. krusei to azoles is not due to the structural features of CYP51 of this microorganism, but rather to another mechanism. Promising ligands that demonstrated sufficiently strong binding in the micromolar range to C. krusei CYP51 were identified, including compounds 99 (Kd = 1.02 ± 0.14 µM) and Ch-4 (Kd = 6.95 ± 0.80 µM). The revealed structural features of the interaction of ligands with the active site of C. krusei CYP51 can be taken into account in the further development of new selective modulators of the activity of this enzyme. [ABSTRACT FROM AUTHOR]

The mortality rates of invasive fungal infections remain high because of the limited number of antifungal drugs available and antifungal drug resistance, which can rapidly evolve during treatment. Mutations in key resistance genes such as ERG11 were postulated to be the predominant cause of antifungal drug resistance in the clinic. However, recent advances in whole genome sequencing have revealed that there are multiple mechanisms leading to the microevolution of resistance. In many fungal species, resistance can emerge through ERG11-independent mechanisms and through the accumulation of mutations in many genes to generate a polygenic resistance phenotype. In addition, genome sequencing has revealed that full or partial aneuploidy commonly occurs in clinical or microevolved in vitro isolates to confer antifungal resistance. This review will provide an overview of the mutations known to be selected during the adaptive microevolution of antifungal drug resistance and focus on how recent advances in genome sequencing technology have enhanced our understanding of this process. [ABSTRACT FROM AUTHOR]

Reactive oxidant species (ROS) are unstable, highly reactive molecules that are produced by cells either as byproducts of metabolism or synthesized by specialized enzymes. ROS can be detrimental, e.g., by damaging cellular macromolecules, or beneficial, e.g., by participating in signaling. An increasing body of evidence shows that various fungal species, including both yeasts and molds, increase ROS production upon exposure to the antifungal drugs currently used in the clinic: azoles, polyenes, and echinocandins. However, the implications of these findings are still largely unclear due to gaps in knowledge regarding the chemical nature, molecular origins, and functional consequences of these ROS. Because the detection of ROS in fungal cells has largely relied on fluorescent probes that lack specificity, the chemical nature of the ROS is not known, and it may vary depending on the specific fungus-drug combination. In several instances, the origin of antifungal drug-induced ROS has been identified as the mitochondria, but further experiments are necessary to strengthen this conclusion and to investigate other potential cellular ROS sources, such as the ER, peroxisomes, and ROS-producing enzymes. With respect to the function of the ROS, several studies have shown that they contribute to the drugs' fungicidal activities and may be part of drug-induced programmed cell death (PCD). However, whether these "pro-death" ROS are a primary consequence of the antifungal mechanism of action or a secondary consequence of drug-induced PCD remains unclear. Finally, several recent studies have raised the possibility that ROS induction can serve an adaptive role, promoting antifungal drug tolerance and the evolution of drug resistance. Filling these gaps in knowledge will reveal a new aspect of fungal biology and may identify new ways to potentiate antifungal drug activity or prevent the evolution of antifungal drug resistance. [ABSTRACT FROM AUTHOR]

Data on antifungal susceptibility of Cryptococcus neoformans are limited in Japan. A total of 89 C. neoformans strains isolated from 83 non-human immunodeficiency virus-infected patients with cryptococcosis between 1997 and 2021 in Nagasaki, Japan, were investigated. Using the reference method M27-Ed4 by the Clinical and Laboratory Standards Institute, the minimum inhibitory concentration for 90% of isolates of fluconazole, itraconazole, voriconazole, amphotericin B, and flucytosine were 4, 0.125, 0.06, 0.5, and 4 µg/ml, respectively, which were below the reported epidemiological cutoff values, without any detectable non-wild-type strains. Our findings imply no increasing trend of antifungal-resistant C. neoformans in Nagasaki, Japan. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is the most prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCR-based tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs.

Historically, fungi were mainly identified as plant and insect pathogens since they grow at 28°C. At the same time, bacteria are known to be the most common human pathogens as they are compatible with the host body temperature of 37°C. Because of immunocompromised hosts, cancer therapy, and malnutrition, fungi are rapidly gaining attention as human pathogens. Over 150 million people have severe fungal infections, which lead to approximately more than one million deaths per year. Moreover, diseases like cancer involving long-term therapy and prophylactic use of antifungal drugs in high-risk patients have increased the emergence of drug-resistant fungi, including highly virulent strains such as Candida auris. This clinical spectrum of fungal diseases ranges from superficial mucocutaneous lesions to more severe and life-threatening infections. This review article summarizes the effect of hospital environments, especially during the COVID-19 pandemic, on fungal infections and emerging pathogens. The review also provides insights into the various antifungal drugs and their existing challenges, thereby driving the need to search for novel antifungal agents.

Wenying Cai,1,* Qianqian Ruan,2– 4,* Jiahao Li,1 Li Lin,1 Liyan Xi,1,5 Jiufeng Sun,2,3 Sha Lu1 1Department of Dermatology and Venereology, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Institute of Public Health, Guangzhou, People’s Republic of China; 3Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, People’s Republic of China; 4School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 5Dermatology Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sha Lu, Department of Dermatology and Venereology, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, 107 West Yanjiang Road, Guangzhou, People’s Republic of China, Email lush7@mail.sysu.edu.cn Jiufeng Sun, Guangdong Provincial Center for Disease Control and Prevention, 160 Qunxian Road, Guangzhou, People’s Republic of China, Email sunjiuf@163.comBackground: Deep fungal infection has become an important cause of infection and death in hospitalized patients, and this has worsened with increasing antifungal drug resistance.Objective: A 3-year retrospective study was conducted to investigate the clinical characteristics, pathogen spectrum, and drug resistance of deep fungal infection in a regional hospital of Guangzhou, China.Methods: Non-duplicate fungi isolates recovered from blood and other sterile body fluids of in-patients of the clinical department were identified using biochemical tests of pure culture with the API20C AUX and CHROMagar medium. Antifungal susceptibilities were determined by Sensititre YeastOne® panel trays.Results: In this study, 525 patients (283 female, 242 male) with deep fungal infection were included, half of them were elderly patients (≥ 60 years) (54.67%, n=286). A total of 605 non-repetitive fungi were finally isolated from sterile samples, of which urine specimens accounted for 66.12% (n=400). Surgery, ICU, and internal medicine were the top three departments that fungi were frequently detected. The mainly isolated fungal species were Candida albicans (43.97%, n=266), Candida glabrata (20.00%, n=121), and Candida tropicalis (17.02%, n=103), which contributed to over 80% of fungal infection. The susceptibility of the Candida spp. to echinocandins, 5-fluorocytosine, and amphotericin B remained above 95%, while C. glabrata and C. tropicalis to itraconazole were about 95%, and the dose-dependent susceptibility of C. glabrata to fluconazole was more than 90%. The echinocandins had no antifungal activity against Trichosporon asahi in vitro (MIC90> 8 μg/mL), but azole drugs were good, especially voriconazole and itraconazole (MIC90 = 0.25 μg/mL).Conclusion: The main causative agents of fungal infection were still the genus of Candida. Echinocandins were the first choice for clinical therapy of Candida infection, followed with 5-fluorocytosine and amphotericin B. Azole antifungal agents should be used with caution in Candida glabrata and Candida tropicalis infections.Keywords: fungal infection, species distribution, antifungal drugs, drug susceptibility, drug resistance

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.

Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.

Background: Repurposing antifungal drugs in cancer therapy has attracted unprecedented attention in both preclinical and clinical research due to specific advantages, such as safety, high-cost effectiveness and time savings compared with cancer drug discovery. The surprising and encouraging efficacy of antifungal drugs in cancer therapy, mechanistically, is attributed to the overlapping targets or molecular pathways between fungal and cancer pathogenesis. Advancements in omics, informatics and analytical technology have led to the discovery of increasing “off-site“ targets from antifungal drugs involved in cancerogenesis, such as smoothened (D477G) inhibition from itraconazole in basal cell carcinoma. Aim of review: This review illustrates several antifungal drugs repurposed for cancer therapy and reveals the underlying mechanism based on their original target and “off-site” target. Furthermore, the challenges and perspectives for the future development and clinical applications of antifungal drugs for cancer therapy are also discussed, providing a refresh understanding of drug repurposing. Key scientific concepts of review: This review may provide a basic understanding of repurposed antifungal drugs for clinical cancer management, thereby helping antifungal drugs broaden new indications and promote clinical translation.

The trend of increasing incidence of skin diseases of various etiologies and the frequency of complications caused by them (dermatitis, allergies, secondary infections, eczema, trichophytosis, dermatophytosis, dermatomycosis, etc.) is increasing in Ukraine. Nowadays the important problem is the development of new domestic effective medicines to combat this pathology. The general market of veterinary drugs, feed additives of finished feed, and premixes was investigated, and the place of drugs used to combat fungal diseases of animal skin was determined to identify the current state and prospects for the development of domestic veterinary drugs (DVD) production. It is established that the studied range of the market saturation structure of veterinary drugs, feed additives, finished feeds, and premixes have significant competition in the pharmaceutical market of Ukraine from foreign manufacturers. The range of effective domestic medicines for the treatment of fungal skin diseases of animals based on domestic substances is very minor, so there are prospects for the introduction into production and further promotion of new effective drugs in this area on the domestic market. The aim of the work is to determine the current state and prospects for the development of the production of national veterinary medicines for the treatment of fungal diseases of animal skin based on the study of the structure of the general market for veterinary drugs, feed additives, finished feed, premixes and determination of their market share. Materials and methods. The following methods (synthetic, analytical, information search, descriptive, generalization) were used in the work. The research materials were literary sources that contain information on the structure of the veterinary market of antifungal and antimicrobial drugs and the “List of Registration of Veterinary Drugs, Feed Additives, and Finished Feeds” as of July 21, 2022. Results. According to the above List, it was found that as of 21.07.2022, 6574 trade names of these products were registered on the Ukrainian market of veterinary medicines, feed additives, finished feed, and premixes. 5097 (77.53 %) of which were supplied by foreign manufacturers, the rest – 1497 (22.47 %) were products of domestic manufacturers. The geography of suppliers is represented by 47 countries, including Ukraine. France, Poland, and Germany remain the leaders in terms of the number of registered items of drugs, feed additives, finished feeds, and premixes. Based on the marketing analysis, it was found that in terms of dosage forms, this market is overly heterogeneous and is represented by 31 dosage forms, which are powders, liquid, solid, soft, and gaseous forms by consistency. It has been proved that a small assortment of antifungal DVDs makes it possible to saturate this segment of the pharmaceutical market not only with imported drugs, but also to find opportunities for the creation and introduction of fundamentally new antifungal DVDs to the domestic market. Conclusions. The development and introduction of new antifungal drugs to the market for further use in the treatment of skin diseases are important. It will contribute to improving the effectiveness of prevention and treatment of the above diseases and will allow the offering of effective innovative pharmacotherapeutic drugs to domestic veterinary practice.

Fungi have a great ability and a wide variety of mechanisms to endure the toxicity of current antifungal agents. Researchers are working to find new therapeutic agents to combat the resistance ability of fungi. Almost all commercial antifungal agents have a wide variety of side effects on human health. This study aims to introduce tea tree oil nanoparticles as antifungal delivery termed TNSAD, which contains hybrid tea tree oil attached chitosan in a liposomal formulation, and assess its antifungal activity using in vitro and in vivo infection models. Tea tree oil was first coated by chitosan, then inserted inside liposomal bilayers, and finally functionalized by a layer of chitosan, forming the TNSAD. The antifungal activity was evaluated against four different invasive, opportunistic, and zoonotic fungal pathogens (Aspergillus flavus, Aspergillus fumigatus, Microsporum gypsum, and Fusarium oxysporum). The cytotoxicity of TNSAD was then tested against the HEp-2 cell line. Finally, the antifungal activity against Aspergillus fumigatus and Microsporum gypsum was assessed in vivo in a rat model. The in vitro results confirm the potency of TNSAD against fungi and its safety at a concentration of ≤ 5 mg/ml. In vivo results revealed that fungal cells were destroyed within the tissue when used systematically. we have described here a natural remarkable design that represents a potential antifungal agent and provided evidence for its efficiency and safety, which makes it a promising antifungal agent for the treatment of systemic and topical fungal infections.