Search Results (110)

Candida auris is an emerging multidrug-resistant fungal pathogen with a high affinity for skin colonization and significant potential for nosocomial transmission. This study aimed to develop and evaluate chitosan-based hydrogels loaded with nystatin and propolis as a topical antifungal strategy for skin decolonization of C. auris. The formulations were selected based on our previous results and optimized for cutaneous application. The internal structure of the hydrogels was investigated by polarized light microscopy, confirming the amorphous nature of propolis and the partial dispersion of nystatin. The antifungal activity was assessed against ten fluconazole-resistant C. auris strains. The CS-NYS-PRO1 formulation demonstrated the highest antifungal performance in the agar test, also reducing viable cell counts to undetectable levels within 6 h. Time–kill assays and SEM imaging confirmed the rapid fungicidal effect and revealed severe membrane disruption and cytoplasmic leakage. Molecular docking analyses indicated the strong binding of nystatin to both sterol 14α-demethylase (CYP51) and dihydrofolate reductase (DHFR) from C. auris, suggesting complementary membrane and intracellular mechanisms of action. These findings support the use of such hydrogels as a local, non-invasive, and biocompatible strategy for managing C. auris colonization, with promising implications for clinical use in infection control and the prevention of skin-mediated transmission in healthcare settings. Full article

Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC₉₀ of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells. Full article

The enormous potential of bacteriotherapy in disease treatment and prevention has created a large probiotic market. Significant challenges exist in assessing probiotic quality, efficacy and viability. Lactic acid bacteria (LAB) are commonly used probiotics and the most abundant of the vertebrate microbiota. The goal of this study was to make MRS agar specific for probiotic Ligilactobacillus animalis NP51, since the current formulation is not sufficiently selective. Here, 53 chemicals were screened to identify compound(s) that reduced the growth of non-LAB and fungi on de Mann, Rogosa, and Sharpe (MRS) agar, and which were selective for LAB and specifically the probiotic strain NP51. Cattle feed was selected as the sample type, as it is commonly amended with Lactobacillus or yeast probiotics and often includes silage, a diverse microbial consortium of fungi and LAB. Modified MRS was evaluated for its effectiveness in determining probiotic viability and the detection of L. animalis NP51 in cattle feed, amended with this probiotic. qPCR was used to specifically detect and enumerate NP51 in commercial and experimental feed samples. For four selective agents, nystatin, guanidine hydrochloride, CuSO₄, and ZnCl, it was identified that when used together, they reduced the growth of bacteria and fungi, but did not inhibit the Lactobacillus probiotic NP51 and other LAB. Metagenomic analysis revealed LAB as the major group cultivated on modified MRS agar from the plating of cattle feed amended with silage. As an enrichment, modified MRS broth improved the qPCR detection of probiotic strain NP51. This study illustrated that improvements can be made to existing bacteriological media for enumerating probiotic NP51 and determining the product’s viability. Full article

Cytokinins, plant hormones derived from adenine, are best known for regulating growth and stress responses in plants. Recent findings suggest they may also influence microbial viability, yet their direct antimicrobial potential remains underexplored. This study evaluates the antimicrobial activities of four natural cytokinins (iPA, B, K, and p-T) and their N⁹-ribosides (iPAR, BR, KR, and p-TR) against selected human pathogens. Using the broth microdilution method, we assessed their effects on Gram-positive and Gram-negative bacteria, as well as fungal strains. While Gram-negative species showed no susceptibility, all tested compounds exhibited bacteriostatic activity against Bacillus subtilis and Enterococcus faecalis. Most notably, kinetin (K) and kinetin riboside (KR) displayed strong antifungal activity against Candida albicans, with MIC values comparable to the reference drug nystatin. Molecular docking studies supported these findings by showing that K and KR form favorable interactions with two validated antifungal targets in Candida albicans: secreted aspartic proteinase 3 (SAP3) and dihydrofolate reductase (DHFR). This is, to our knowledge, the first report linking natural cytokinins to direct antifungal action against C. albicans supported by in silico evidence. These findings highlight the potential of K and KR as promising leads for the development of cytokinin-based antifungal agents. Full article

Background: Fungal infections, particularly among immunocompromised individuals, present significant challenges due to rising incidence rates, treatment costs, and increasing resistance to antifungal agents. This study evaluates trends in antifungal use among Medicaid beneficiaries, focusing on prescribing patterns, costs, and pricing to optimize therapy. Methods: Using the national Medicaid outpatient pharmacy claims data collected by the US Center of Medicare and Medicaid Services, a retrospective drug utilization analysis was conducted for antifungal medications from 2009 to 2023. Antifungal medications were categorized based on therapeutic use. The study examined annual utilization, reimbursement, and pricing trends, along with the market share. Results: Overall Medicaid utilization of superficial fungal infections’ (SFIs’) medications increased from 3.95 million prescriptions in 2009 to 6.16 million in 2023. Nystatin was the most frequently utilized SFI agent, while fluconazole emerged as the most commonly prescribed agent for invasive fungal infections (IFIs). In 2022, a notable spike occurred in the number of prescriptions for both SFIs and IFIs. Medicaid’s total expenditure on SFI medications rose from USD 121.9 million in 2009 to USD 155 million in 2023, while spending on IFI medications fluctuated substantially, peaking at USD 156.8 million in 2022 before declining to USD 80.7 million in 2023. After being introduced to the market, efinaconazole became the most expensive SFI agent over the years. Isavuconazole, the latest approved IFI medication, demonstrated sustained utilization, reimbursement, and price increases. Conclusions: The substantial rise in antifungal utilization and spending underscores the growing financial burden on Medicaid, emphasizing the need for policy interventions to manage costs and generic drug substitution while ensuring equitable access to these essential treatments. However, this study is limited by the lack of clinical outcome data and information on off-label use. Additionally, reimbursement data may not accurately reflect actual drug prices. Full article

Integrating soft components into denture design may significantly enhance the comfort of edentulous patients. Microorganisms, particularly Candida albicans, often colonize soft denture lining materials, which can release metabolic and toxic byproducts linked to the development of Denture-Induced Stomatitis. This study aimed to evaluate the effectiveness of antimicrobial agents incorporated into soft denture liners in inhibiting the adhesion and colonization of C. albicans. A systematic review was conducted through MEDLINE-Pubmed, EMBASE, and the Cochrane Central Register of Controlled Trials. A range of keywords was employed without applying a time filter to identify relevant literature. The review revealed many studies investigating various antimicrobial compounds added to different soft denture liner materials, all demonstrating the ability to inhibit the proliferation of C. albicans. All the antimicrobial agents examined exhibited a significant antifungal effect, with minimal to negligible impact on the physical properties of the denture liners. However, it was noted that the mechanical properties of the liners were modified in direct correlation to the concentration of the antimicrobial agents utilized. The successful incorporation of these agents into various soft denture liners has been documented, with nystatin being the primary pharmacological agent identified across multiple studies. While incorporating antibacterial agents was deemed successful, it is essential to note that the methodologies employed yielded varying effects on the overall performance of the soft-liner materials. Full article

Background/Objectives: Aerobic vaginitis (AV) and bacterial vaginosis (BV) are vaginal infections requiring the fast elimination of pathogens. The frequent confusion of these infections may justify the use of a rapidly acting broad-spectrum antibiotic treatment. Methods: This study investigated the bactericidal kinetics of the neomycin-polymyxin B-nystatin (NPN) combination compared to those of two reference antibiotics (clindamycin and metronidazole) against 22 bacteria commonly implicated in AV and BV. Results: NPN exhibited bactericidal activity against the aerobic Gram-positive bacteria, with particularly high bactericidal activity being observed against streptococci, S. aureus, and C. amycolatum after 1 h at low dilutions and after 4 h for all dilutions. Enterococci were less sensitive to NPN. Clindamycin demonstrated poor rapid bactericidal activity against all Gram-positive bacteria tested. NPN manifested high bactericidal activity against all aerobic Gram-negative bacteria tested, whereas clindamycin showed bactericidal activity only after 4 h at a 1/2 dilution. With respect to the four anaerobic strains tested, NPN demonstrated high bactericidal activity at all tested dilutions with concentration-dependent effects. Metronidazole exhibited lower or no rapid bactericidal activity. Conclusions: These results suggest that NPN has very fast bactericidal action against the main bacteria involved in AV and BV compared to clindamycin and metronidazole, highlighting its potential in managing bacterial vaginal infections. Full article

Fusarium wilt of banana (FWB), caused by Fusarium oxysporum f. sp. cubense (Foc) tropical race 4 (TR4), poses a severe threat to the global banana industry. The screening of endophytic fungi from the mangrove plant led to the identification of Medicopsis sp. SCSIO 40440, which exhibited potent antifungal activity against Fusarium. The further fraction of the extract yielded ten compounds, including MK8383 (1) and nine new analogues, MK8383s B-J (2–10). The structures of 1–10 were elucidated using extensive spectroscopic data and single-crystal X-ray diffraction analysis. In vitro antifungal assays revealed that 1 showed strongly antifungal activities against Foc TR4, with an EC₅₀ of 0.28 μg/mL, surpassing nystatin and hygromycin B (32 and 16 μg/mL, respectively). Pot experiments showed that 1 or spores of SCSIO 40440 could significantly reduce the virulence of Foc TR4 on Cavendish banana. Full article

Fungal infections are a significant global public health challenge because of their widespread occurrence, morbidity, and profound social and economic consequences. Antifungal resistance is also an increasing concern, posing a substantial risk to public health. There is a growing interest in searching for new antifungal drugs isolated from natural sources. This study aimed to evaluate the antifungal activity of novel mollusk fractions against fungal strains resistant to nystatin and amphotericin B. In addition, the role of oxidative stress in the mechanism of damage was determined. The mucus from the garden snail Cornu aspersum (MCa/1-20) and the hemolymph fraction from the marine snail Rapana venosa (HLRv/3-100) were obtained and characterized via 12% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric -analyses. The results demonstrate that the spores and biomass of both mollusk fractions have a significant fungicidal effect against Penicillium griseofulvum, and Aspergillus niger. Compared to the control group, the release of intracellular proteins and reducing sugars was significantly increased in the treated groups. The data showed increased levels of oxidative stress biomarkers (lipid peroxidation and oxidatively damaged proteins) and a downregulated antioxidant enzyme defense, corresponding to increased antifungal activity. To our knowledge, this is the first study evaluating oxidative stress as a factor in mollusk fractions’ antifungal activity. Full article

Clinical and mycological data are essential for the optimal management of patients with Candida vaginitis (CV), particularly in cases of (i) azole-resistant C. albicans vaginitis, (ii) recurrent CV, and (iii) CV in pregnant women. The present retrospective single-center study investigated the antifungal activity of six commonly used antifungals against randomly selected vaginal isolates recovered from 68 pregnant women in Adana, Türkiye, including C. albicans, petite C. glabrata, non-petite C. glabrata, and C. krusei, using the disk diffusion method at pH 4 and 7. Furthermore, the antifungal activities of fluconazole and itraconazole were also assessed using the broth microdilution method. For all isolates, the mean inhibition zone diameters were narrower for itraconazole and ketoconazole and larger for miconazole at pH 4 than pH 7 (p < 0.05). For nystatin, zone diameters were wider in C. albicans and petite C. glabrata at pH 4 (p < 0.001 and p < 0.001). Remarkably, clotrimazole was more active at pH 4 than at pH 7, except against non-petite C. glabrata isolates. Based on the broth microdilution results, the resistance rate was higher at pH 4 than at pH 7 in all isolates. Candida glabrata petite isolates exhibited MIC values 2 to 5 times higher than those of the non-petite isolates for both fluconazole and itraconazole. This study highlights the potent activity of topical antifungals (miconazole, nystatin, and clotrimazole) for the treatment of CV in pregnant women and highlights the need to identify petite and non-petite mutants of vaginal C. glabrata isolates to obtain more reliable data and for antifungal susceptibility testing prior to decision-making. The results of the two antifungal susceptibility methods were compared for C. albicans and C. glabrata isolates, and the reliability of the disk diffusion test was discussed. Full article

Essential oils are investigated due to their biological activity, and the Amazon rainforest, with its rich biodiversity, is a promising source of therapeutic compounds. The aim of this study was to evaluate the essential oil from the leaves of Bixa orellana as an antifungal agent, thus contributing to the search for alternatives that can address the growing resistance to conventional antifungals. B. orellana leaves were collected in the Ecuadorian Amazon and their essential oil was obtained by steam distillation. Their chemical composition was analysed by Gas Chromatography-Mass Spectrometry (GC-MS) and their antifungal activity against Candida albicans was evaluated using the Kirby–Bauer disc diffusion method (ATCC 10231), with nystatin as a positive control. GC-MS analysis revealed the presence of 60 compounds, the main ones being dihydroedulan (27.5%), β-caryophyllene (10.3%), nerolidol (7.21%), trans-β-bergamotene (5.73%), α-santalene (4.94%) and trans-α-bergamotene (4.26%). The essential oil showed moderate antifungal activity against C. albicans, producing an inhibition halo of 13 mm in diameter, which is 48% of the inhibition observed with nystatin (27 mm). The presence of sesquiterpenes, such as β-caryophyllene, known for its membrane-disrupting properties, probably contributes to the observed antifungal effects. The study highlights the potential of B. orellana essential oil as a natural antifungal agent; however, further research is required to evaluate its efficacy against a wider range of pathogenic fungi, its possible synergistic effects with conventional antifungals and its safety and efficacy in vivo. Full article

Background: Recently, pyrido[2,3-d] pyrimidine, triazolopyrimidine, thiazolopyrimidine, quinoline, and pyrazole derivatives have gained attention due to their diverse biological activities, including antimicrobial, antioxidant, antitubercular, antitumor, anti-inflammatory, and antiviral effects. Objective: The synthesis of new heterocyclic compounds including 5-quinoline-pyrido[2,3-d] pyrimidinone (1–2, 4, 6–7), 6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (3, 5, 8–10), 1,2,4-triazole-6-quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidinone (11–13), and pyrido[2,3-d]thiazolo[3,2-a]pyrimidine-ethyl-(pyridine)-9-thiaazabenzo[cd]azulenone (14) derivatives was performed with high yields while evaluating antimicrobial activities. Methods: A new series of quinoline-pyrido[2,3-d]thiazolo[3,2-a]pyrimidine derivatives were prepared using a modern style and advanced technology, resulting in high yields of these new compounds. Various reagents were utilized, specifically tailored to the production needs of each compound, through reactions that included alkylation, addition, condensation, acylation, the formation of Schiff bases, and intramolecular cyclization. Results: The chemical structures of the new compounds were determined using spectroscopy analyses, including IR, NMR, and MS, achieving good yields ranging from 68% to 90% under mild conditions in a regular system. All compounds were tested for in vitro antimicrobial activity and compared to standard drugs, specifically cefotaxime sodium and nystatin. The results showed that compounds 10 to 14 exhibited excellent antimicrobial activity, with a minimum inhibitory concentration (MIC) of 1 to 5 µmol/mL, compared to that of the standard drugs, which had MIC values of 1 to 3 µmol/mL. Furthermore, molecular docking studies were conducted to explore the interactions of specific compounds with antimicrobial target proteins. The findings revealed that compounds 10 to 14 displayed significant binding energies, with ΔG values ranging from −7.20 to −11.70 kcal/mol, indicating effective binding to the active sites of antimicrobial protein receptors. Conclusions: The SAR study confirmed a relationship between antimicrobial activity and the tested compounds. Molecular docking demonstrated that compounds 10, 11, 12, 13, and 14 exhibited significant binding energy, effectively interacting with the active sites of antimicrobial protein receptors. This consistent finding supports that these new compounds’ practical and theoretical studies align regarding their antimicrobial activity. Full article

Objectives: In 2022, the World Health Organization highlighted the necessity for the development of new antifungal agents. Polyene antibiotics are characterized by a low risk of drug resistance; however, their use is limited by low solubility and severe side effects. Methods: A series of N-alkylated derivatives of amphotericin B and nystatin A₁ as well as their N-(2-hydroxyethyl)amides were synthesized. Their antifungal activity was evaluated against various Candida strains and Aspergillus fumigatus using the broth microdilution method. Cytotoxicity was assessed using an MTT assay on human embryonic kidney cells HEK293 and human skin fibroblast cells hFB-hTERT6, as well as a hemolysis assay on erythrocytes. Membrane activity was analyzed by fluorimetric measurement of calcein leakage from model liposomes. Results: Derivatives containing the N-(hydroxyethyl)amino)ethyl fragment (compounds 3 and 4) exhibited relatively high antifungal activity, as did N-(2-hydroxyethyl)amides 5 and 9. Bis-modified compounds 6 and 10 did not outperform their mono-modified analogues in terms of activity or cytotoxicity. The mono-N-alkylated compound 3 showed the highest activity/toxicity ratio, which correlated well with its selectivity for ergosterol-containing model membranes. Discussion: Combining two successful modifications does not necessarily improve the activity/toxicity ratio of polyenes. Further studies can be performed for the optimization of carboxyl group of 3. Full article

Currently, the rising prevalence of resistant Candida species, particularly Candida albicans, as well as non-albicans isolates such as Candida glabrata and Candida krusei, represent challenges in their management. In this review, we aimed to explore the current management of fluconazole-resistant vulvovaginal candidiasis (FRVVC). Identified studies focused on alternative antifungal therapies, including boric acid, nystatin, and newer agents like oteseconazole and ibrexafungerp. The findings highlight the need for tailored treatment regimens, considering the variability in resistance patterns across regions. Unprofessional as well as professional overuse of antifungals for vulvovaginal symptoms that are not caused by Candida infections should be combatted and banned as much as possible. Instead of high-dose maintenance regimens using weekly doses of 150 to 200 mg of fluconazole for 6 months or longer, it is advisable to use an individualised degressive regimen (ReCiDiF regimen) in order to tailor the treatment of a particular patient to the lowest dosage possible to keep the diseases controlled. Additionally, this report underscores the impact of antibiotic use on the microbiota, which can raise the possibility of VVC and lead to fluconazole resistance, emphasizing the necessity for cautious antibiotic prescribing practices. Full article

The primary cause of postharvest loss in table grape fruit is attributed to gray mold, which is caused by Botrytis cinerea. The present study confirmed the inhibitory effects of nystatin on the growth and development of B. cinerea, which led to a remarkable reduction in the severity of gray mold on table grape fruits. Furthermore, the application of nystatin disrupted the membrane permeability of B. cinerea, causing increased cellular leakage and cell death. In addition, the transcriptome analysis showed that the application of nystatin effectively modulated the transcriptional profile of genes involved in ribosome and mitochondrion biogenesis, as well as oxidoreductase activity, thereby disrupting the homeostasis of cellular organelles. Moreover, the nystatin treatment down-regulated genes associated with membrane trafficking, protein degradation by the ubiquitin–proteasome system, and the autophagy process, ultimately attenuating the pathogenicity of B. cinerea. Collectively, nystatin can be considered a viable agent for managing gray mold on table grape fruit. Full article