Antifungal Chemotherapy Research Articles

Natural Substances as Valuable Alternative for Improving Conventional Antifungal Chemotherapy: Lights and Shadows.

Fungi are eukaryotic organisms with relatively few pathogenic members dangerous for humans, usually acting as opportunistic infections. In the last decades, several life-threatening fungal infections have risen mostly associated with the worldwide extension of chronic diseases and immunosuppression. The available antifungal therapies cannot combat this challenge because the arsenal of compounds is scarce and displays low selective action, significant adverse effects, and increasing resistance. A growing isolation of outbreaks triggered by fungal species formerly considered innocuous is being recorded. From ancient times, natural substances harvested from plants have been applied to folk medicine and some of them recently emerged as promising antifungals. The most used are briefly revised herein. Combinations of chemotherapeutic drugs with natural products to obtain more efficient and gentle treatments are also revised. Nevertheless, considerable research work is still necessary before their clinical use can be generally accepted. Many natural products have a highly complex chemical composition, with the active principles still partially unknown. Here, we survey the field underlying lights and shadows of both groups. More studies involving clinical strains are necessary, but we illustrate this matter by discussing the potential clinical applications of combined carnosic acid plus propolis formulations.

A novel lentiviral vector-based approach to generate chimeric antigen receptor T cells targeting Aspergillus fumigatus.

Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated from peripheral blood mononuclear cells of four healthy human donors and expanded with either of three cytokine stimulation regimens (IL-2, IL-2 + IL-21, or IL-7 + IL-15) significantly suppressed mycelial growth of AF-293 after 18 hours of co-culture and synergized with the immunomodulatory antifungal agent caspofungin to control hyphal growth for 36 hours. Moreover, cyclophosphamide-immunosuppressed NSG mice with invasive pulmonary aspergillosis that received two doses of 5 million AF-CAR T cells (6 and 48 hours after AF infection) showed significantly reduced morbidity on day 4 post-infection (P < 0.001) and significantly improved 7-day survival (P = 0.049) compared with mice receiving non-targeting control T cells, even without concomitant antifungal chemotherapy. In conclusion, we developed a novel lentiviral strategy to obtain AF-CAR T cells with high targeting efficacy, yielding significant anti-AF activity in vitro and short-term protection in vivo. Our approach could serve as an important steppingstone for future clinical translation of antifungal CAR T-cell therapy after further refinement and thorough preclinical evaluation.IMPORTANCEInvasive aspergillosis (IA) remains a formidable cause of morbidity and mortality in patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation. Despite the introduction of several new Aspergillus-active antifungals over the last 30 years, the persisting high mortality of IA in the setting of continuous and profound immunosuppression is a painful reminder of the major unmet need of effective antifungal immune enhancement therapies. The success of chimeric antigen receptor (CAR) T-cell therapy in cancer medicine has inspired researchers to translate this approach to opportunistic infections, including IA. Aiming to refine anti-Aspergillus CAR T-cell therapy and improve its feasibility for future clinical translation, we herein developed and validated a novel antibody-based CAR construct and lentiviral transduction method to accelerate the production of CAR T cells with high targeting efficacy against Aspergillus fumigatus. Our unique approach could provide a promising platform for future clinical translation of CAR T-cell-based antifungal immunotherapy.

Synthesis, characterization, crystallographic aspects, Fukui function, and photodynamic antifungal chemotherapy investigation of Cd(II)-tricyanomethanide coordination polymer: Insights from DFT

Synthesis, characterization, crystallographic aspects, Fukui function, and photodynamic antifungal chemotherapy investigation of Cd(II)-tricyanomethanide coordination polymer: Insights from DFT

Role of Antifungal Therapy in Treating different Types of Fungal Infections and it’s Future: A Systematic Review

An estimated 20-25 percent of the world's population has a fungal infection, which is most commonly a Trichophyton type of infection, making fungal disease infection one of the most common types of infection worldwide. Due to drug resistance and changes in the morphology of the fungi, treating fungal infections in humans is one of the most difficult cases to cure. Since 1960, the discovery of systemic antifungal chemotherapy has made a substantial contribution to the treatment of the majority of human fungal infections. Antifungal agents' chemotherapy rely completely on their ability to disrupt the integrity of the plasma membrane, cell wall, cell metabolism, mitotic activity, or inhibit fungal cell formation. Topically (to treat local infections) or systemically (to heal skin infections) antifungal treatments are available (systemic infections treatment). Structure, solubility, mode of action, pharmacokinetics, activity spectrum, therapeutic impact (fungicidal or fungistatic), and toxicity are all characteristics of antifungal medicines. The emerging of multi-drug-resistant fungal diseases has given rise to a new class of fungal infections. The availability of medications that target fungal cells rather than human cells further restricts pharmaceutical options for treating fungal infections. A brief systematic overview of the types of fungal infections, characteristics of antifungal medicines, and the future of antifungal therapy has been clearly stated in the current review so that it can be utilised in further upcoming study.

Azole derivatives inhibit wildtype butyrylcholinesterase and its common mutants.

Azoles, which have been used for antifungal chemotherapy for decades, have recently been of interest for their efficacy against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). There is little known about the potential of azoles against BChE, however there is none regarding their inhibitory effects against mutants of BChE. In the current study, an azole library of 1-aryl-2-(1H-imidazol-1-yl)ethanol/ethanone oxime esters were tested against AChE and BChE, which yielded derivates more potent than the positive control, galantamine, against both isoforms. Kinetic analyses were performed for wildtype and mutant (A328F and A328Y) inhibition for the two most potent BChE inhibitors, pivalic and 3-bezoylpropanoic acid esters of 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanol, which were found to have great affinity to the wildtype and mutant BChE types with Ki values as low as 0.173 ± 0.012 µM. The compounds were identified to show linear competitive or mixed type inhibition. Molecular modeling confirmed these kinetic data and provided further insights regarding molecular basis of BChE inhibition by the active derivatives. Thus, current study suggests new azole derivatives with promising cholinesterase inhibitory effects and reveals the first set of information to promote our understanding for the inhibitory behavior of this class against the mutant BChE forms.

Antifungal chemotherapies and immunotherapies for the future.

Human fungal pathogens cause a broad plethora of infections, spanning cutaneous dermatophytoses to invasive infections in immunocompromised hosts. As eukaryotic pathogens are capable of morphotype switching, they present unique challenges both for drug development and the immunological response. Whilst current antifungal therapies are limited to the orally available triazoles, intravenous echonocandins and polyenes, and flucytosine and terbinafine, there has been recent significant progress in the antifungal armamentorium with ibrexafungerp, a novel orally available terpanoid that inhibits 1,3-beta-D-glucan-approved by Food and Drug Administration in 2021, and fosmanogepix, an orally available pro-drug of manogepix, which targets glycosylphosphatidylinositol-anchored protein maturation entering Phase 3 studies for candidaemia. A number of further candidates are in development. There has been significant use of existing immunotherapies such as recombinant interferon-γ and G-CSF for fungal disease in immunocompromised patients, and there are emerging opportunities for monoclonal antibodies targeting TH2 inflammation. Omalizumab, an anti-IgE monoclonal antibody in asthma, is now used routinely for the treatment of allergic bronchopulmonary aspergillosis, and further agents targeting IL-4 and IL-5 are being evaluated. In addition, T-cell CAR therapy is showing early promise for fungal disease. Thus, we are likely to see rapid advances to our approach to the management of fungal disease in the near future.

Targeting DNA Topoisomerase II in Antifungal Chemotherapy.

Topoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand the range of therapeutic options. In this review paper, we discussed the usefulness of fungal topo II as a molecular target for new drug discovery. On the basis of previously published data, we described structural and biochemical differences between fungal and human enzymes as well as a molecular basis of differential sensitivity to known anticancer drugs targeting the latter. This review focuses especially on highlighting the differences that may underlie the selectivity of action of new inhibitors. Distinct sites within fungal topo II in comparison with human counterparts are observed and should be further studied to understand the significance of those sites and their possible usage in design of new drugs.

Menthol Inhibits Candida albicans Growth by Affecting the Membrane Integrity Followed by Apoptosis.

Inclusion of Candida albicans in the list of pathogens with potential drug resistance threat in recent years has compelled scientists to explore novel and potent antifungal agents. In this study, we have evaluated anti-Candida potential of menthol against different growth forms and synergistic potential with fluconazole. Menthol inhibited planktonic growth of all the isolates completely at ≤3.58 mM and killed 99.9% inoculum at MIC, indicating that menthol is fungicidal. Menthol inhibited hyphal form growth completely at 0.62 mM. It has inhibited developing a biofilm by 79% at 3.58 mM, exhibiting excellent activity against recalcitrant biofilms. FIC index values of 0.182 and 0.093 indicate excellent synergistic activity between fluconazole and menthol against planktonic and biofilm growth, respectively. Menthol enhanced rate of OxPhos among 22% cells; arrested 71% cells at G2-M phase of cell cycle and induced apoptosis in 15% cells. Thus, menthol exhibits excellent anti-Candida activity against differentially susceptible isolates as well as various growth and morphological forms of C. albicans. Menthol affects membrane integrity thereby inducing oxidative stress followed by cell cycle arrest and apoptosis. Considering the excellent anti-Candida potential and as it is Generally Recognized as Safe by the Food and Drug Administration, it may find use in antifungal chemotherapy, alone or in combination.

Curcumin affects function of Hsp90 and drug efflux pump of Candida albicans.

Candida albicans is a pathogenic yeast that causes candidiasis in immunocompromised patients. The overuse of antifungal drugs has led to the development of resistance to such drugs by this fungus, which is a major challenge in antifungal chemotherapy. One approach to this problem involves the utilization of new natural products as an alternative source of antifungals. Curcumin, one such natural product, has been widely studied as a drug candidate and is reported to exhibit antifungal activity against C. albicans. Although studies of the mechanism of curcumin against human cancer cells have shown that it inhibits heat shock protein 90 (Hsp90), little is known about its function against C. albicans. In this paper, using a doxycycline-mediated HSP90 strain and an HSP90-overexpressing strain of C. albicans, we demonstrated that the curcumin triggered a decrease in Hsp90 by affecting it at the post-transcriptional level. This also led to the downregulation of HOG1 and CDR1, resulting in a reduction of the stress response and efflux pump activity of C. albicans. However, the inhibition of HSP90 by curcumin was not due to the inhibition of transcription factors HSF1 or AHR1. We also found that curcumin can not only decrease the transcriptional expression of CDR1, but also inhibit the efflux pump activity of Cdr1. Hence, we conclude that disruption of HSP90 by curcumin could impair cell growth, stress responses and efflux pump activity of C. albicans.

P054 Two effects of curcumin to Candida albicans

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMObjectives Candida albicans is a pathogenic yeast that causes candidiasis in immunocompromised patients. The overuse of antifungal drugs has led to the development of resistance to such drugs by this fungus, which is a major challenge in antifungal chemotherapy. The utilization of natural products is a significant trial for the development of new antifungals. Curcumin, one such natural product, has been widely studied as a drug candidate and is reported to exhibit antifungal activity against C. albicans. Although studies of the mechanism of curcumin against human cancer cells have shown that it inhibits heat shock protein 90 (Hsp90), little is known about its molecular function against C. albicans. In this work, we investigated the relationship between curcumin and Hsp90 of C. albicans.MethodsFor the molecular genetical analyses of C. albicans Hsp90, a doxycycline-mediated HSP90 strain and a HSP90-overexpressing strain of this fungus were constructed. The effect of curcumin on the gene expression of HSF1, AHR1, HOG1, and CDR1 as well as HSP90 was analyzed. Moreover, the stress responses to high temperature and osmotic pressure and the drug efflux of these strains were investigated.ResultsCurcumin reduced the transcription of HSP90 at the post-transcriptional level and it was suggested to lead to the decrease in Hsp90. This phenomenon resulted in the downregulation of HOG1 and CDR1. In addition, we confirmed curcumin also inhibited Cdr1 efflux activity in C. albicans.ConclusionCurcumin was suggested to influence not only HSP90 expression but also Cdr1 activity in C. albicans.

Antifungal Effect of Penicillamine Due to the Selective Targeting of L-Homoserine O-Acetyltransferase.

Due to the apparent similarity of fungal and mammalian metabolic pathways, the number of established antifungal targets is low, and the identification of novel ones is highly desirable. The results of our studies, presented in this work, indicate that the fungal biosynthetic pathway of L-methionine, an amino acid essential for humans, seems to be an attractive perspective. The MET2 gene from Candida albicans encoding L-homoserine O-acetyltransferase (CaMet2p), an enzyme catalyzing the first step in that pathway, was cloned and expressed as the native or the oligo-His-tagged fusion protein in Escherichia coli. The recombinant enzymes were purified and characterized for their basic molecular properties and substrate specificities. The purified MET2 gene product revealed the appropriate activity, catalyzed the conversion of L-homoserine (L-Hom) to O-acetyl-L-homoserine (OALH), and exhibited differential sensitivity to several L-Hom or OALH analogues, including penicillamine. Surprisingly, both penicillamine enantiomers (L- and D-Pen) displayed comparable inhibitory effects. The results of the docking of L- and D-Pen to the model of CaMet2p confirmed that both enantiomeric forms of the inhibitor are able to bind to the catalytic site of the enzyme with similar affinities and a similar binding mode. The sensitivity of some fungal cells to L-Pen, depending on the presence or absence of L-Met in the medium, clearly indicate Met2p targeting. Moreover, C. glabrata clinical strains that are resistant to fluconazole displayed a similar susceptibility to L-Pen as the wild-type strains. Our results prove the potential usefulness of Met2p as a molecular target for antifungal chemotherapy.

A Specific Mixture of Propolis and Carnosic Acid Triggers a Strong Fungicidal Action against Cryptococcus neoformans.

Current antifungal chemotherapy against the prevalent basidiomycete Cryptococcus neoformans displays some drawbacks. This pathogenic fungus is refractory to echinocandins, whereas conventional treatment with amphotericin B plus 5-fluorocytosine has a limited efficacy. In this study, we explored the potential cryptococcal activity of some natural agents. After conducting a screening test with a set of propolis from different geographical areas, we selected an extract from China, which displayed a certain cytotoxic activity against C. neoformans, due to this extract being cheap and easily available in large amounts. The combination of this kind of propolis with carnosic acid in a 1:4 ratio induced a stronger fungicidal effect, which occurred following a synergistic pattern, without visible alterations in external cell morphology. Furthermore, several carnosic acid–propolis formulations applied onto preformed biofilms decreased the metabolic activity of the sessile cells forming biofilms. These data support the potential application of mixtures containing these two natural extracts in the design of new antifungal strategies in order to combat opportunistic infections caused by prevalent pathogenic fungi.

“Mucormycosis” The Emerging Global Threat – A Complete Review

Mucormycosis is a life-threatening invasive fungal infection that affects people who are immunocompromised (haematological malignancies, solid organ transplantation, diabetes mellitus). Pulmonary, rhinocerebral, cutaneous, and disseminated infections are the most common. Controlling mucormycosis requires reversing the underlying problems. Treatment for mucormycosis also includes quick and vigorous surgery. Extensive surgical debridement of necrotic tissues is required. Finally, an antifungal treatment is required. High-dose liposomal amphotericin B (5 mg/kg/day) is the first-line treatment for mucormycosis. Antifungal chemotherapy has no set length; instead, it is determined by the remission of all related symptoms and results (usually 6-8 weeks). Posaconazole maintenance therapy/secondary prophylaxis should be recommended in patients who have a persistently weakened immune system. Keywords: Mucormycosis, Diabetes mellitus, Liposomal Amphotericin B.

Proteomic analysis of serial isolates of Trichosporon asahii identifies host-specific adaptations using the TMT/MRM approach

The opportunistic fungal pathogen Trichosporon asahii (T. asahii) is an important causal agent of mortality in immunocompromised patients and associated with frequent relapses, even with sufficient antifungal treatment. Investigating the proteomes of initial and recurrent isolates may help to identify within-host adaptive changes. In this study, using tandem mass tag (TMT)-labeling combined with liquid chromatography-mass spectrometry/mass spectrometry (LC–MS/MS) technology, we analyzed the proteomes of two T. asahii strains that were isolated 15 years apart from the same patient who suffered initial and recurrent episodes of systemic disseminated trichosporonosis. A total of 597 differentially expressed proteins were identified. Functional analysis showed that the increased proteins were primarily concentrated on peptide/protein/energy/drug metabolism and translation. Most of the results were determined to be consistent with the findings of phenotypic assays, such as tests for drug susceptibility, temperature growth, biofilm formation, melanization and paromomycin assays. Moreover, we performed multiple reaction monitoring (MRM) mass spectrometry to verify 27 candidate proteins, and the results of this experiment were also highly consistent with the results of the TMT analysis. Therefore, to the best of our knowledge, these data provide the first molecular evidence of how the T. asahii proteome changes related to host-specific adaptation during human infection. SignificanceSystemic infection with Trichosporon asahii (T. asahii) has recently been recognized as an important causal agent of mortality in immunocompromised patients. Although triazole treatment usually works efficiently in the early phase of infection, many patients relapse. Hence, comparative analyses of the proteomics of initial and recurrent isolates may reveal evidence of adaptive changes within the host. Our study demonstrates that the recurrent strain has undergone proteomic changes using tandem mass tag (TMT)-labeling combined with liquid chromatography-mass spectrometry/mass spectrometry (LC–MS/MS). Moreover, the results of phenotypic assays, including drug susceptibility, temperature growth, biofilm formation, melanization and paromomycin assays, were highly consistent with the proteomic changes, and multiple reaction monitoring (MRM) verification also showed similar trends to the TMT results. In summary, our study is the first to investigate the adaptation of T. asahii under pressure from antifungal chemotherapy and host immune responses.

Rapid screening method of Saccharomyces cerevisiae mutants using calcofluor white and aniline blue.

Fungal cell walls are composed of polysaccharide scaffold that changes in response to environment. The structure and biosynthesis of the wall are unique to fungi, with plant and mammalian immune systems evolved to recognize wall components. Additionally, the enzymes that assemble fungal cell wall components are excellent targets for antifungal chemotherapies and fungicides. Understanding changes in the cell wall are important for fundamental understanding of cell wall dynamics and for drug development. Here we describe a screening technique to monitor the gross morphological changes of two key cell wall polysaccharides of chitin and β-1,3-glucan combined with polymerase chain reaction (PCR) genotyping. Changes in chitin and β-1,3-glucan were detected microscopically by using the dyes calcofluor white and aniline blue. Combining PCR and fluorescence microscopy, as a quick and easy screening technique, confirmed both the phenotype and genotype of the wild-type, h chitin synthase mutants (chs1Δ and chs3Δ) and one β-1,3-glucan synthase mutant fks2Δ from Saccharomyces cerevisiae knockout library. This combined screening method highlighted that the fks1Δ strain obtained commercially was in fact not FKS1 deletion strain, and instead had both wild-type genotype and phenotype. A new β-1,3-glucan synthase knockout fks1::URA3 strain was created. Fluorescence microscopy confirmed its phenotype revealing that the chitin and the new β-1,3-glucan profiles were elevated in the mother cells and in the emerging buds respectively in the fks1Δ cell walls. This combination of PCR with fluorescence microscopy is a quick and easy screening method to determine and verify morphological changes in the S. cerevisiae cell wall.

Organic Antifungal Drugs and Targets of Their Action.

In recent decades, there has been a significant increase in the number of fungal diseases. This is due to a wide spectrum of action, immunosuppressants and other group drugs. In terms of frequency, rapid spread and globality, fungal infections are approaching acute respiratory infections. Antimycotics are medicinal substances endorsed with fungicidal or fungistatic properties. For the treatment of fungal diseases, several groups of compounds are used that differ in their origin (natural or synthetic), molecular targets and mechanism of action, antifungal effect (fungicidal or fungistatic), indications for use (local or systemic infections), and methods of administration (parenteral, oral, outdoor). Several efforts have been made by various medicinal chemists around the world for the development of antifungal drugs with high efficacy with the least toxicity and maximum selectivity in the area of antifungal chemotherapy. The pharmacokinetic properties of the new antimycotics are also important: the ability to penetrate biological barriers, be absorbed and distributed in tissues and organs, get accumulated in tissues affected by micromycetes, undergo drug metabolism in the intestinal microflora and human organs, and in the kinetics of excretion from the body. There are several ways to search for new effective antimycotics: - Obtaining new derivatives of the already used classes of antimycotics with improved activity properties. - Screening of new chemical classes of synthetic antimycotic compounds. - Screening of natural compounds. - Identification of new unique molecular targets in the fungal cell. - Development of new compositions and dosage forms with effective delivery vehicles. The methods of informatics, bioinformatics, genomics and proteomics were extensively investigated for the development of new antimycotics. These techniques were employed in finding and identification of new molecular proteins in a fungal cell; in the determination of the selectivity of drugprotein interactions, evaluation of drug-drug interactions and synergism of drugs; determination of the structure-activity relationship (SAR) studies; determination of the molecular design of the most active, selective and safer drugs for the humans, animals and plants. In medical applications, the methods of information analysis and pharmacogenomics allow taking into account the individual phenotype of the patient, the level of expression of the targets of antifungal drugs when choosing antifungal agents and their dosage. This review article incorporates some of the most significant studies covering the basic structures and approaches for the synthesis of antifungal drugs and the directions for their further development.

1159. Echinocandins Dosing in Obese Patients: A Systematic Review

BackgroundEchinocandins are a milestone in antifungal chemotherapy given their fungicidal properties with improved toxicity profiles compared to other antifungal agents. Echinocandins are used in the empiric treatment of invasive candidiasis and aspergillosis in critically ill, neutropenic, and transplant patients. There is emerging evidence that obese patients treated with echinocandins antifungal agents have lower plasma serum concentration and faster clearance. The objective of this review was to systematically evaluate the available evidence for echinocandins dosing in obese patients.MethodsA systematic review of PubMed, Embase, Cochrane library from inception until June 8, 2020 was conducted by 2 authors. Studies with data for micafungin, anidulafungin, or caspofungin in obese patients’ exposure [body mass index (BMI) 30 or greater] were included. Studies for patients on renal replacement therapies, extracorporeal membrane oxygenation support, and language other than English were excluded.ResultsTwenty-five studies met the inclusion criteria; micafungin (n=10), caspofungin (n=8), and anidulafungin (n=7). In micafungin, the correlation between obesity and increasing systemic clearance and reduced exposure was reported. Some studies reported even lower systemic exposure with morbid obesity, BMI greater than 40. The evidence was also consistent with anidulafungin, two studies revealed that body weight had inverse correlation with anidulafungin exposure. Anidulafungin exposure was about 30% lower in obese patients. Furthermore, caspofungin exposure was also reduced in obese patient as demonstrated in several studies.ConclusionAdequate antifungal exposure is a key in success treatment, and there are several factors that can influence exposure of echinocandin antifungal agents. There is consistent evidence revealing lower echinocandins exposure in obese patient. Research is needed to determine outcomes of fungal infections of obese patients, and perhaps the need for dose adjustment in obese patient population.Disclosures All Authors: No reported disclosures

Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies.

Azole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. Compound 73's minimum inhibitory concentration (MIC) value less than 1 μg/ml against S. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistant S. aureus (MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.

Treatment of abdominal granuloma and hypercalcaemia caused by Cladophialophora bantiana with combination antifungal chemotherapy and hyperbaric oxygen therapy in a dog

A 5-year-old intact male Boxer was evaluated for a 4-month history of ventral abdominal mass with fistulous tracts. Thoracic and abdominal CT revealed a large soft-tissue mass in the rectus...

Cerebellar Cryptococcoma in an Immunocompetent Adult: A Rare Occurrence Report of a Case and Review of Literature

AbstractThis study reports a rare case of cryptococcoma of the brain and review the related literature. An intracranial lesion, in a healthy, middle-aged adult who underwent surgery with a preoperative diagnosis of neoplastic/metastatic lesion, which turned out to be cryptococcoma, is being reported. Histopathological examination revealed that this immunocompetent patient had cryptococcoma of the cerebellum. He responded to antifungal chemotherapy (amphotericin B initially for 2 weeks and later oral fluconazole for 10 weeks) very well. Occurrence of cryptococcomas in immunocompetent patients is rare and responds to antifungal chemotherapy very well. Only six cases (including this) have been reported in literature till now.