Treatment Of Fungal Infections Research Articles

Obtention, characterization and cytotoxicity of fixed oils from Elaeocarpus serratus: a remarkable vegetable oil

The specie Elaeocarpus serratus belonging to the Elaeocarpaceae family is popularly known as Ceylon Olive and used medicinally for the treatment of bacterial and fungal infections. The fruits contain tannins and fatty acids in fixed oils (FO). The specie adapts well to the conditions of the soil and climate of Brazil and, due to the good productivity of fruits that the plant presents, it shows potential in the production of FO. Despite its uses, there are no studies that provide more details on the characterization and obtaining of oils from this species. The objective of this study was aimed to characterize the obtention and properties of the oil seed to verify the yield and the potential use. The FOs were obtained by the Soxhlet extraction method and analyzed through the parameters refractive, acidity and saponification indexes. From the FOs obtained, the seeds resulted in the highest yield (1.71%), followed by pericarps with seeds (1.01%) and pericarps (0.49%). The FOs were submitted to the lethality test of Artemia saline as a predictor of cytotoxicity, obtaining percentages of lethality of 76% for seed oil. The high cytotoxicity shown by the OFs corroborates with the antimicrobial and antifungal uses of the species and the indexes tested showed that the oil obtained from the seed demonstrates potential application in products with industrial, cosmetic and pharmaceutical interests.

Antifungal activity of Fe3O4@SiO2/Schiff-base/Cu(II) magnetic nanoparticles against pathogenic Candida species

The antifungal efficacy and cytotoxicity of a novel nano-antifungal agent, the Fe3O4@SiO2/Schiff-base complex of Cu(II) magnetic nanoparticles (MNPs), have been assessed for targeting drug-resistant Candida species. Due to the rising issue of fungal infections, especially candidiasis, and resistance to traditional antifungals, there is an urgent need for new therapeutic strategies. Utilizing Schiff-base ligands known for their broad-spectrum antimicrobial activity, the Fe3O4@SiO2/Schiff-base/Cu(II) MNPs have been synthesized. The Fe3O4@SiO2/Schiff-base/Cu(II) MNPs was characterized by Fourier Transform-Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), Energy-dispersive X-ray (EDX), Vibrating Sample Magnetometer (VSM), and Thermogravimetric analysis (TGA), demonstrating successful synthesis. The antifungal potential was evaluated against six Candida species (C. dubliniensis, C. krusei, C. tropicalis, C. parapsilosis, C. glabrata, and C. albicans) using the broth microdilution method. The results indicated strong antifungal activity in the range of 8–64 μg/mL with the lowest MIC (8 μg/mL) observed against C. parapsilosis. The result showed the MIC of 32 μg/mL against C. albicans as the most common infection source. The antifungal mechanism is likely due to the disruption of the fungal cell wall and membrane, along with increased reactive oxygen species (ROS) generation leading to cell death. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay for cytotoxicity on mouse L929 fibroblastic cells suggested low toxicity and even enhanced cell proliferation at certain concentrations. This study demonstrates the promise of Fe3O4@SiO2/Schiff-base/Cu(II) MNPs as a potent antifungal agent with potential applications in the treatment of life-threatening fungal infections, healthcare-associated infections, and beyond.

Antifungal drug resistance in Candida: a special emphasis on amphotericin B.

Invasive fungal infections in humans caused by several Candida species, increased considerably in immunocompromised or critically ill patients, resulting in substantial morbidity and mortality. Candida albicans is the most prevalent species, although the frequency of these organisms varies greatly according to geographic region. Infections with C. albicans and non-albicans Candida species have become more common, especially in the past 20 years, as a result of aging, immunosuppressive medication use, endocrine disorders, malnourishment, extended use of medical equipment, and an increase in immunogenic diseases. Despite C. albicans being the species most frequently associated with human infections, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei also have been identified. Several antifungal drugs with different modes of action are approved for use in clinical settings to treat fungal infections. However, due to the common eukaryotic structure of humans and fungi, only a limited number of antifungal drugs are available for therapeutic use. Furthermore, drug resistance in Candida species has emerged as a result of the growing use of currently available antifungal drugs against fungal infections. Amphotericin B (AmB), a polyene class of antifungal drugs, is mainly used for the treatment of serious systemic fungal infections. AmB interacts with fungal plasma membrane ergosterol, triggering cellular ion leakage via pore formation, or extracting the ergosterol from the plasma membrane inducing cellular death. AmB resistance is primarily caused by changes in the content or structure of ergosterol. This review summarizes the antifungal drug resistance exhibited by Candida species, with a special focus on AmB.

Deep Eutectic Solvent Eutectogels for Delivery of Broad-Spectrum Antimicrobials.

Gel-based wound dressings have gained popularity within the healthcare industry for the prevention and treatment of bacterial and fungal infections. Gels based on deep eutectic solvents (DESs), known as eutectogels, provide a promising alternative to hydrogels as they are non-volatile and highly tunable and can solubilize therapeutic agents, including those insoluble in hydrogels. A choline chloride:glycerol-cellulose eutectogel was loaded with numerous antimicrobial agents including silver nanoparticles, black phosphorus nanoflakes, and commercially available pharmaceuticals (octenidine dihydrochloride, tetracycline hydrochloride, and fluconazole). The eutectogels caused >97% growth reduction in Gram-positive methicillin-resistant Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa bacteria and the fungal species Candida albicans.

Divergent mitochondrial responses and metabolic signal pathways secure the azole resistance in Crabtree-positive and negative Candida species.

Azole drugs are the main therapeutic drugs for invasive fungal infections. However, azole-resistant strains appear repeatedly in the environment, posing a major threat to human health. Several reports have shown that mitochondria are associated with the virulence of pathogenic fungi. However, there are few studies on the mechanisms of mitochondria-mediated azoles resistance. Here, we first performed mitochondrial proteomic analysis on multiple Candida species (Candida albicans, Nakaseomyces glabrata, Pichia kudriavzevii, and Candida auris) and analyzed the differentially expressed mitochondrial proteins (DEMPs) between azole-sensitive and azole-resistant Candida species. Subsequently, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology analysis, and protein-protein interaction network analysis of DEMPs. Our results showed that a total of 417, 165, and 25 DEMPs were identified in resistant C. albicans, N. glabrata, and C. auris, respectively. These DEMPs were enriched in ribosomal biogenesis at cytosol and mitochondria, tricarboxylic acid cycle, glycolysis, transporters, ergosterol, and cell wall mannan biosynthesis. The high activations of these cellular activities, found in C. albicans and C. auris (at low scale), were mostly opposite to those observed in two fermenter species-N. glabrata and P. kudriavzevii. Several transcription factors including Rtg3 were highly produced in resistant C. albicans that experienced a complex I activation of mitochondrial electron transport chain (ETC). The reduction of mitochondrial-related activities and complex IV/V of ETC in N. glabrata and P. kudriavzevii was companying with the reduced proteins of Tor1, Hog1, and Snf1/Snf4.IMPORTANCECandida spp. are common organisms that cause a variety of invasive diseases. However, Candida spp. are resistant to azoles, which hinders antifungal therapy. Exploring the drug-resistance mechanism of pathogenic Candida spp. will help improve the prevention and control strategy and discover new targets. Mitochondria, as an important organelle in eukaryotic cells, are closely related to a variety of cellular activities. However, the role of mitochondrial proteins in mediating azole resistance in Candida spp. has not been elucidated. Here, we analyzed the mitochondrial proteins and signaling pathways that mediate azole resistance in Candida spp. to provide ideas and references for solving the problem of azole resistance. Our work may offer new insights into the connection between mitochondria and azoles resistance in pathogenic fungi and highlight the potential clinical value of mitochondrial proteins in the treatment of invasive fungal infections.

Quinalizarin as a potential antifungal drug for the treatment of Candida albicans fungal infection in cancer patients.

This study aims to analyze the antifungal properties of quinalizarin, a plant-derived compound with proven anticancer effects. Quinalizarin exhibited antifungal activity against opportunistic pathogenic Candida species and Geotrichum capitatum. The treatment with this anthraquinone reduced hyphal growth, inhibited biofilm formation, and damaged mature Candida albicans biofilms. Real-time RT-PCR revealed that quinalizarin downregulated the expression of hyphae-related and biofilm-specific genes. The flow cytometry method used in the study showed that both apoptosis and necrosis were the physiological mechanisms of quinalizarin-induced C. albicans cell death, depending on the dose of the antifungal agent. A further study revealed an increase in the levels of intracellular reactive oxygen species and alterations in mitochondrial membrane potential after treatment with quinalizarin. Finally, quinalizarin was found to have low toxicity in a hemolytic test using human erythrocytes. In conclusion, we have identified quinalizarin as a potential antifungal compound.IMPORTANCEThis article is a study to determine the antifungal activity of quinalizarin (1,2,5,8-tetrahydroxyanthraquinone). Quinalizarin has potential antitumor properties and is effective in different types of tumor cells. The aim of the present study was to prove that quinalizarin can be used simultaneously in the treatment of cancer and in the treatment of intercurrent fungal infections. Quinalizarin was identified as a novel antifungal compound with low toxicity. These results may contribute to the development of a new drug with dual activity in the treatment of cancer-associated candidiasis.

An ethnobotanical survey investigating medicinal plants used by Cape bush doctors to treat dermatophyte infections

IntroductionOver the past few years, the incidence of dermatophyte infections has increased at an alarming rate. The treatment for these infections is becoming more difficult especially because fungal pathogens have developed resistance to conventional treatments. The Cape Metropole region in South Africa has an abundance of plant species and is the residence of herbalists, called Cape bush doctors who use some of these diverse plants to treat various skin-related conditions. There are limited ethnobotanical studies that have been conducted on the medicinal plants they use to treat dermatophyte infections. Therefore, this study aimed to report on the knowledge and practices of Cape bush doctors concerning their use of medicinal plants for treating dermatophyte infections. MethodologyA cross-sectional study was performed using an interview-based questionnaire to investigate (1) the knowledge of bush doctors regarding skin infections, (2) the practices of bush doctors along with the medicinal plants used when treating fungal skin infections, and (3) selected plants identified with potential anti-fungal activity in vitro, were further explored to assess their application in the treatment of fungal infections by bush doctors. ResultsParticipants confirmed the use of the fifteen selected medicinal plants identified in the literature. Additionally, twenty other plant species were mentioned as having antifungal properties. Most plants reported belonged to the Xanthorrhoeaceae, Amaryllidaceae, Asteraceae, Lamiaceae, and Rutaceae families. ConclusionThis study shows that bush doctors use a vast array of plant species to treat dermatophyte conditions. This indicates the diversity of medicinal plant species used and that these doctors associated indigenous knowledge is of great value. Therapeutic uses of the documented plants provide data for further pharmacological studies.

DEFB114 protein enhances host resistance to fungal infection through the NOD1/2-ATG16L1-NF-κB signaling pathway

The overuse of antibiotics has led to the enhanced resistance of many pathogenic bacteria, posing a threat to human health. Therefore, there is a need to develop green and safe alternatives to antibiotics. Beta-defensins play a crucial role in host defense against pathogens and have multifunctional properties, exerting key roles in innate and adaptive immunity, as well as non-immune processes. In this study, a 210 bp long cDNA sequence of yak DEFB114 gene was amplified and successfully expressed in a prokaryotic system. The DEFB114 protein exhibited significant inhibitory effects on the growth of Aspergillus fumigatus in vitro. When co-cultured with yak macrophages, DEFB114 protein enhanced macrophage phagocytic activity and increased nucleic acid fluorescence intensity (P < 0.05). DEFB114 protein also enhanced the activity of yak macrophages stimulated by inactivated Aspergillus fumigatus spores, increased the release of nitric oxide (NO), and promoted the expression of genes such as γ-actin, Lgals, Man2b, and Capg (P < 0.05). In mice experiments, DEFB114 protein promoted resistance against Aspergillus fumigatus infection, by regulating the NOD1/2-ATG16L1-NF-κB pathway to modulate the host immune response and exert its anti-infective effects. In summary, the yak DEFB114 protein could inhibit the growth of Aspergillus fumigatus and enhance the animal's resistance to pathogenic microorganisms, thereby having significant implications in the treatment and prevention of fungal infections.

New Approaches to Overcoming Antimicrobial Resistance in Endophthalmitis.

Endophthalmitis is a rare but vision-threatening infection characterized by marked inflammation of intraocular fluids and tissues, uncommonly seen following surgery and intravitreal injection. Antimicrobials are used worldwide in the prophylaxis and treatment of bacterial and fungal infections of the eye and are standard treatment in the preoperative and postoperative care of surgical patients. However, antimicrobials are reported to be overprescribed in many parts of the world, which contributes to antimicrobial resistance (AMR). AMR complicates the prophylaxis and treatment of endophthalmitis. This article examines the prevalence and mechanisms of AMR in ocular microorganisms, emphasizing the importance of understanding AMR patterns for tailored treatments. It also explores prophylaxis and management strategies for endophthalmitis, with a discussion on the use of intracameral antibiotic administration. The use of prophylactic intracameral antibiotics during cataract surgery is common in many parts of the world but is still controversial in some locations, especially in the US. Finally, it highlights the role of stewardship in ophthalmology and its benefits in the treatment of endophthalmitis.

Anti-infective treatment of fungal infections by Candida and Aspergillus

Anti-infective treatment of fungal infections by Candida and Aspergillus

A mechanism study on the synergistic effects of rifapentine and fluconazole against fluconazole-resistant Candida albicans in vitro

Candida albicans (C. albicans) is one of the most common clinical isolates of systemic fungal infection. Long-term and inappropriate use of antifungal drugs can cause fungal resistance, which poses a great challenge to the clinical treatment of fungal infections. The combination of antifungal drugs and non-antifungal drugs to overcome the problem of fungal resistance has become a research hotspot in recent years. Our previous study found that the combination of rifapentine (RFT) and fluconazole (FLC) has a significant synergistic against FLC-resistant C. albicans. The present study aimed to further verify the synergistic effect between FLC and RFT against the FLC-resistant C. albicans 100, and explore the underlying mechanism. The growth curve and spot assay test not only showed the synergistic effect of FLC and RFT on FLC-resistant C. albicans in vitro but exhibited a dose-dependent effect on RFT, indicating that RFT may play a principal role in the synergic effect of the two drugs. Flow cytometry showed that the combined use of RFT and FLC arrested cells in the G2/M phase, inhibiting the normal division and proliferation of FLC-resistant C. albicans. Transmission electron microscopy (TEM) demonstrated that FLC at a low concentration could still cause a certain degree of damage to the cell membrane in the FLC-resistant C. albicans, as represented by irregular morphologic changes and some defects observed in the cell membrane. When FLC was used in combination with RFT, the nuclear membrane was dissolved and the nucleus was condensed into a mass. Detection of the intracellular drug concentration of fungi revealed that the intracellular concentration of RFT was 31–195 fold that of RFT alone when it was concomitantly used with FLC. This indicated that FLC could significantly increase the concentration of RFT in cells, which may be due to the damage caused to the fungal cell membrane by FLC. In short, the present study revealed a synergistic mechanism in the combined use of RFT and FLC, which may provide a novel strategy for the clinical treatment of FLC-resistant C. albicans.

Nitrogen-doped carbon quantum dots as a novel treatment for black fungal bone infections (Mucormycosis): in vitro and in vivo study

Most fungal bone and joint infections (arthritis) are caused by Mucormycosis (Mucor indicus). These infections may be difficult to treat and may lead to chronic bone disorders and disabilities, thus the use of new antifungal materials in bone disorders is vital, particularly in immunocompromised individuals, such as those who have contracted coronavirus disease 2019 (COVID-19). Herein, we reported for the first time the preparation of nitrogen-doped carbon quantum dots (N/CQDs) and a nitrogen-doped mesoporous carbon (N/MC) using a quick micro-wave preparation and hydrothermal approach. The structure and morphology were analysed using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and surface area analyser. Minimum inhibitory concentration (MIC), disc diffusion tests, minimum fungicidal concentration (MFC) and antifungal inhibitory percentages were measured to investigate the antifungal activity of N/CQDs and N/MC nanostructures. In addition to the in vivo antifungal activity in rats as determined by wound induction and infection, pathogen count and histological studies were also performed. According to in vitro and in vivo testing, both N/CQDs with small size and N/MC with porous structure had a significant antifungal impact on a variety of bone-infecting bacteria, including Mucor infection. In conclusion, the present investigation demonstrates that functional N/CQDs and N/MC are effective antifungal agents against a range of microbial pathogenic bone disorders in immunocompromised individuals, with stronger and superior fungicidal activity for N/CQDs than N/MC in vitro and in vivo studies.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study

Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Pharmacokinetics of amphotericin B after accidental overdose in an adult critically ill patient treated with plasmapheresis: a case report and review of literature

Amphotericin B is a broad-spectrum antifungal agent that is used in the treatment of systemic fungal infections. We describe the case of a 62-year-old female patient with recent aneurysmal subarachnoid hemorrhage who was treated for suspected ventriculitis and a fungal coinfection. Instead of liposomal amphotericin B (L-AmB), 465 mg (5 mg/kg) amphotericin B deoxycholate (DOC) was inadvertently administered, leading to refractory shock with multiple organ failure and requiring mechanical ventilation. Since an overdose of amphotericin B can lead to fatal consequences and has a half-life of 15 days, plasmapheresis was started. The serum concentration decreased from 1.32 µg/mL to 0.62 µg/mL before plasmapheresis, demonstrating a mean half-life of 49 hours. After two plasmapheresis sessions, the serum concentration further dropped to 0.26 µg/mL, demonstrating a mean half-life of 17 hours. In contrast, the third plasmapheresis session had no effect on serum concentration. The patient made a full recovery, potentially facilitated by enhanced amphotericin B elimination through plasmapheresis. Positive outcomes were previously reported in two adult patients treated with plasmapheresis. However, other reports without plasmapheresis described fatal outcomes in adult patients, albeit with a twofold overdose compared to the two patients successfully treated with plasmapheresis. Moreover, plasmapheresis itself carries risks such as hypocalcemia, metabolic alkalosis, and coagulation deficits. Consequently, the role of plasmapheresis in amphotericin B overdose is still debated.

Impact of Anti-Mycotic Drugs on the Osteogenic Response of Bone Marrow Mesenchymal Stem Cells In Vitro.

The treatment of fungal bone infections and infected non-unions is a huge challenge in modern trauma and orthopedics, which normally contain the local and systemic administration of anti-fungal drugs. Although frequently used, little is known about the impact of systemic and locally administered fungicides on the osteogenic regenerative capabilities of infected bone tissue, especially upon the osteogenesis of human bone marrow mesenchymal stem cells (BM-hMSCs). This study evaluates the effects of the three most common fungicides for the systemic treatment of bone infections, Voriconazole (VOR), liposomal Amphotericin B (LAMB), and Fluconazole (FLU), as well as the effects of VOR and LAMB-loaded Polymethylmethacrylate (PMMA) cement chips in different concentrations upon the osteogenic response of BM-hMSCs in vitro. Within this study, we compared the ability of BM-hMSC to differentiate into osteoblast-like cells and synthesize hydroxyapatite as assessed by radioactive 99mTechnetium-Hydroxydiphosphonate (99mTc-HDP) labeling, cell proliferation, and analyses of supernatants upon various osteogenic parameters. Our results revealed that VOR added to the cell culture medium affects the osteogenic potential of BM-hMSC negatively, while there were no detectable effects of LAMB and FLU. Moreover, we showed dose-dependent negative effects of high- and extended-dose fungicide-loaded PMMA cement due to cytotoxicity, with a higher cytotoxic potential of VOR than LAMB, while low-dose fungicide-loaded PMMA had no significant effect on the osteogenic potential of BM-hMSC in vitro.

A potent candicidal peptide designed based on an encrypted peptide from a proteinase inhibitor

Antimicrobial peptides (AMP) represent an alternative in the treatment of fungal infections associated with countless deaths. Here, we report a new AMP, named KWI-19, which was designed based on a peptide encrypted in the sequence of an Inga laurina Kunitz-type inhibitor (ILTI). KWI-19 inhibited the growth of Candida species and acted as a fungicidal agent from 2.5 to 20 μmol L−1, also showing synergistic activity with amphotericin B. Kinetic assays showed that KWI-19 killed Candida tropicalis cells within 60 min. We also report the membrane-associated mechanisms of action of KWI-19 and its interaction with ergosterol. KWI-19 was also characterized as a potent antibiofilm peptide, with activity against C. tropicalis. Finally, non-toxicity was reported against Galleria mellonella larvae, thus strengthening the interest in all the bioactivities mentioned above. This study extends our knowledge on how AMPs can be engineered from peptides encrypted in larger proteins and their potential as candicidal agents.

ON THE 100TH ANNIVERSARY OF THE BIRTH OF SERAFIMA ALEXANDROVNA VICHKANOVA (1924‒2017)

The biographical sketch is dedicated to Serafima Alexandrovna Vichkanova (1924–2017), Doctor of Biological Sciences, Professor, Honored Scientist of the Russian Federation, who worked in the laboratory of antimicrobial and antiviral agents at the All–Russian Research Institute of Medicinal and Aro-matic Plants (Moscow). The main life stages, the scientific directions being developed and the contribution to the formation and development of the field of studying the antimicrobial properties of plants and substances from them in order to create new effective chemotherapeutic agents for the treatment of viral, bacterial, fungal and other infections, as well as a list of the main scientific works are presented in the article

Rational Design of Antifungal Peptides Based on the γ-Core Motif of a Neosartorya (Aspergillus) fischeri Antifungal Protein to Improve Structural Integrity, Efficacy, and Spectrum.

Antifungal peptides offer promising alternative compounds for the treatment of fungal infections, for which new antifungal compounds are urgently needed. Constant and broad antifungal spectra of these peptides play essential roles in their reliable therapeutic application. It has been observed that rationally designed peptides using the evolutionarily conserved γ-core region (GXC-X3-9-C) of an antifungal protein from Neosartorya (Aspergillus) fischeri highly inhibit the growth of fungi. The cysteines in these peptides have free sulfhydryl groups, which allow cyclization and dimerization under oxidative conditions, thereby impairing antifungal efficacy. To overcome this problem, one or two cysteine residues were substituted by serines or S-tert-butyl was applied as a cysteine-protecting group. Furthermore, structural integrity and antifungal efficacy investigations before and after oxidative exposure revealed that substituting both cysteines with serines and S-tert-butylation helped maintain the structural integrity. However, it slightly decreased the antifungal efficacy against a yeast, Candida albicans. Interestingly, S-tert-butylation maintained the efficacy and could extend the antifungal activity to a mold, Aspergillus fumigatus. Usually, cyclization and dimerization did not influence the antifungal efficacy of most peptides. Additionally, hemolysis tests and Galleria mellonella toxicity model experiments indicated that none of the applied modifications made the peptides harmful to animals.

MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. NCT03572049.