Search Results (631)

The treatment of leishmaniasis has limitations due to drug toxicity and the increasing resistance of the parasite. In this study, we analyze the role of oxidative stress in the pathogenesis and treatment of leishmaniasis, as well as in new therapeutic alternatives of natural origin. The evasion mechanisms against the host immune response involve surface molecules present in the parasite, which modulate oxidative stress to ensure its survival. Drug treatment requires strict monitoring to minimize adverse reactions and ensure patient safety, as mechanisms such as lipid peroxidation, mitochondrial dysfunction, and depletion of antioxidant defenses are associated with drug toxicity. Plant-derived products with antileishmanial activity impact the parasite’s redox balance, inducing apoptosis and reducing its parasitic load. Most studies are still in preliminary stages, making in vivo assays and clinical studies essential, along with the development of accessible formulations. Oxidative stress is involved in the pathogenesis of leishmaniasis, as Leishmania manipulates the host’s redox balance to survive. It also contributes to drug toxicity, as antimonials and amphotericin B increase reactive oxygen species, causing cellular damage. Several plant-derived compounds have demonstrated antileishmanial activity by modulating oxidative stress and promoting parasite apoptosis. Examples include alkaloids from Aspidosperma nitidum, lignans from Virola surinamensis, flavonoids from Geissospermum vellosii, and triterpenoids such as β-sitosterol. Although these compounds show promising selectivity, most studies remain in preliminary stages, requiring in vivo assays and clinical studies to confirm efficacy and safety, as well as the development of affordable formulations. Full article

Background: Anti-mold azoles have improved the outcomes of invasive aspergillosis (IA) when used therapeutically, but they are extensively used as prophylaxis. There are limited data regarding the outcomes of patients with hematologic malignancy who develop breakthrough IA on anti-mold azoles. We aimed to determine whether breakthrough IA on azole prophylaxis shows worse outcomes compared to no prophylaxis. Methods: We compared outcomes including therapy response and mortality between antifungal regimens in hematologic malignancy patients with IA between July 1993 and July 2023. Results: Compared to an amphotericin B-containing regimen (AMB), an anti-mold azole as the primary therapy was independently associated with successful response at the end of therapy (OR = 4.38, p < 0.0001), protective against 42-day IA-associated mortality (OR = 0.51, p = 0.024) or all cause mortality (OR = 0.35, p < 0.0001), and protective against 84-day mortality, both IA-associated (OR = 0.50, p = 0.01) and all-cause mortality (OR = 0.27, p < 0.0001). Azole prophylaxis was independently associated with higher IA-associated mortality at 42 days (OR = 1.91, p = 0.012) and 84 days (OR = 2.03, p = 0.004), compared to fluconazole or no prophylaxis. Conclusions: Patients with breakthrough IA on anti-mold azole prophylaxis show a worse prognosis than those on other or no prophylaxis, possibly related to the emergence of azole resistance due to their widespread use as prophylaxis agents. On the other hand, anti-mold azole primary therapy is superior to AMB therapy in the treatment of IA. Full article

Leishmania is a protozoan parasite causing a spectrum of pathologies in humans grouped under the name leishmaniasis. Clinical outcomes range from the self-healing cutaneous form to the visceral one that is fatal in the absence of treatment. The leishmaniases are endemic in 98 countries in the tropics, subtropics, and Southern Europe, where 3 million new cases and more than 50,000 deaths are recorded yearly. Control of this disease is challenging as there is no approved vaccine coupled with toxic chemotherapeutics and the development of parasite resistance to some available drugs. It is, therefore, evident that the identification of new control methods, including new therapeutics, should be strongly encouraged. In the present study, thiol organic compounds were synthesized and tested for their activity against Leishmania major, the causative agent of human cutaneous leishmaniasis. Of the 21 compounds tested, 13 were active against L. major promastigotes in vitro at 100 μg/mL. Selected compounds tested in a dose-response assay showed activity at concentration as low as 25 μg/mL, a level of activity similar to that of Amphotericin B, a drug of choice for the treatment of human leishmaniasis. Structure–activity analysis shows that the addition of certain substituents, such as a methoxy group, to a compound that is biologically active renders it inactive. Together, our data demonstrate that functionalized thiols have an in vivo anti-Leishmania activity that is directly linked to their chemical structure. Full article

Cryptococcal infections are distributed worldwide and mainly caused by Cryptococcus neoformans and Cryptococcus gattii. The reduced number of antifungals and increasing number of cases of resistance require the search for new therapeutic options, such as natural products. Among these, Punica granatum L. has demonstrated antifungal activity. The present study aimed to evaluate the in vitro activity of the hydroethanolic extract of the leaf of P. granatum (HEPg) alone or in antifungal combination against C. neoformans and C. gattii and the interference of P. granatum in the mitochondrial membrane of Cryptococcus using flow cytometry. The minimum inhibitory concentration was determined, which showed inhibitory activity against Cryptococcus isolates. The fractional inhibitory concentration resulted in an indifferent interaction between the combination of amphotericin B + HEPg, whereas the combination of fluconazole + HEPg was synergistic against C. gattii. The depolarisation of mitochondrial membranes was more pronounced when C. gattii was previously treated with P. granatum, either individually or in combination with antifungal agents. In contrast, prior treatment of C. gattii with fluconazole promoted the hyperpolarisation of mitochondrial membranes. Considering the growing search for alternative forms of treatment for cryptococcosis, this study highlights the antifungal potential of P. granatum. Full article

Leishmaniasis, a complex disease caused by protozoal parasites of the genus Leishmania, presents various clinical forms, particularly a cutaneous clinical form. Treatment is typically performed with pentavalent antimonial and amphotericin B, both of which have severe side effects that hinder patient compliance. This emphasizes the need for the development of new, effective, and safe treatments. In this study, the leishmanicidal activity of the methanolic extract, an alkaloid-enriched fraction and dicentrine, the main alkaloid of the leaves of Ocotea puberula (Lauraceae), a native Brazilian plant traditionally used by the indigenous population to treat skin affections, was investigated in vitro. Additionally, an in vivo study evaluated the efficacy of a topical cream containing 0.5% dicentrine. The in vitro studies demonstrated high activity and selectivity of methanolic extract, alkaloid-enriched fraction, and dicentrine against the promastigote and amastigote forms of Leishmania (Leishmnia) amazonensis and Leishmania (Viannia) braziliensis. The leishmanicidal effect of dicentrine was related to the modulation of macrophage microbicidal activity. A cream containing 0.5% dicentrine showed high stability and, in permeation studies, dicentrine was retained in a skin-mimicking artificial membrane. This cream effectively inhibited the progression of the skin lesion in BALB/c mice infected with L. (L.) amazonensis, together with a reduced parasite number. Thus, dicentrine offers a promising alternative to the treatment of skin leishmaniasis. Full article

Moesziomyces spp. (Pseudozyma) is a genus recognized as a new opportunistic human pathogen, causing systemic infections including premature neonates and adult patients. These fungi’s natural resistance to caspofungin enables them to spread through vascular catheter colonization, making them a new etiological agent associated with fungal bloodstream infections (FBIs) and a significant contributor to high mortality rates. In this report, we present a case of fungemia caused by Moesziomyces aphidis species in a patient with medical history that revealed pancreatic cancer infiltrating the duodenum and bile ducts. During hospitalization, the M. aphidis was cultured twice from peripheral blood samples on Sabouraud agar. The strain was sensitive to amphotericin B and voriconazole. In vitro susceptibility testing revealed resistance to fluconazole, caspofungin, anidulafungin, and micafungin. Antifungal therapy with voriconazole resulted in the resolution of clinical symptoms associated with fungal infection. Related to M. aphidis fungemia, we reviewed a total of three cases in Europe published in the PubMed database between 2003 and 2024. To the best of our knowledge, this is the first case of M. aphidis FBI in Poland and the fourth case in an adult patient in Europe. 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

Pentavalent antimonials are the first line for leishmaniasis treatment, although they induce many adverse side effects and treatment failure and parasite resistance have been detected. Cutaneous leishmaniasis is the main clinical manifestation of the disease in Oaxaca State, Mexico; however, its presence is under-registered, and information about the Leishmania species that circulate and cause the disease in the region is limited. In this study, the presence of Leishmania was analyzed in 24 skin smears and 2 biopsies from lesions suspicious for leishmaniasis in inhabitants of the Tehuantepec Isthmus and Papaloapan Basin regions, Oaxaca State. By ITS1-PCR, the species of clinical isolates were identified. Moreover, the susceptibility of clinical isolates to leishmanicidal drugs was assessed. Skin smears were negative for the presence of Leishmania spp.; meanwhile, parasite amastigotes were observed in tissue biopsies; however, by ITS1-PCR, 46% of the samples were determined to be positive for the parasite. Six clinical isolates were identified as L. mexicana and had lower susceptibility to Miltefosine and Amphotericin B than the L. mexicana reference strain. No leishmanicidal activity of Glucantime was detected. Further studies with increased patient sample sizes and genotypic studies will describe in detail parasite susceptibility to reference drugs in the region. Full article

Fungi are a typical part of the microbiome of poultry houses, but some of the genera can be pathogenic for poultry and humans. An investigation was conducted on 200 duck eggs from 10 flocks to determine total fungal contamination on the eggshells. The colony types were identified morphologically and microscopically, and a representative group was identified using PCR. The resistance profiles for all obtained Aspergillus isolates were conducted. The dominating genera on eggshells were Penicillium, Alternaria and Aspergillus and the number of fungal colonies ranged from 0 to 7100. Aspergillus fumigatus was cultured from 9.5% eggshells, and all isolates were obtained from three flocks. The minimum inhibitory concentration (MIC) values for A. fumigatus isolates ranged from 0.094–32 μg/mL for amphotericin B (MIC 50 1 mg/L and MIC 90 32 μg/mL), 0.125–32 μg/mL for caspofungin (MIC 50 0.38 μg/mL and MIC 90 32 μg/mL), 0.19–32 μg/mL for itraconazole (MIC 50 1.5 μg/mL and MIC 90 32 μg/mL), 0.047–12 μg/mL for posaconazole (MIC 50 0.5 μg/mL and MIC 90 8 μg/mL) and 0.023–32 μg/mL for voriconazole (MIC 50 0.19 μg/mL and MIC 90 32 μg/mL). A total of 73.7% of the isolates were resistant to posaconazole and 68.4% to itraconazole. Nearly half of the strains (47.4%) showed resistance to amphotericin B and 31.6% to voriconazole. Because of the lack of antifungals registered for poultry, hygiene and the regular disinfection of litter in particular are needed to prevent the contamination of the eggs by fungi for both animal and human health. Full article

Background: Amphotericin B (AmB) is a commonly utilized antifungal agent, which is also recommended for the treatment of certain neglected tropical diseases, including leishmaniasis. However, its clinical application is constrained because of its poor oral bioavailability and adverse effects, prompting the investigation of alternative drug delivery systems. Polymeric nanoparticles (PNPs) have gained attention as a potential drug delivery vehicle, providing advantages such as sustained release and enhanced bioavailability, and could have potential as AmB carriers. However, concerns persist regarding nanomaterials’ toxicity, requiring more studies. Zebrafish (Danio rerio) embryos were used as a valuable model for toxicity testing, especially because of their genetic similarity to humans and standardized developmental assessments. Methods: In this study, we produced and characterized AmB loaded and non-loaded PNPs by nanoprecipitation, dynamic light scattering, transmission electron microscopy, atomic force microscopy and spectroscopy. Afterwards, we verified their toxicity through in vitro MTT assays in three cell lines (HEK293, HepG2, and J774 A1) and in vivo tests with zebrafish embryos. Results: In both trials, it was noted that nanoencapsulation of the drug led to increased toxicity when compared to non-encapsulated AmB, possibly indicating that they penetrated the embryo’s chorion. Nevertheless, it was demonstrated that the polymers used are safe and they are not the cause of toxicity, neither are the nanostructures per se. Conclusions: Therefore, it is believed that the objective of improving the bioavailability of AmB may have been achieved, and the observed toxicity was probably linked to AmB’s ability to destabilize cell membranes. Full article

We present the case of a 60-year-old immunocompromised man who presented with two pruritic pink–red indurated nodules with overlying scale and focal areas of ulceration on his left dorsal and left medial forearm, which evolved over a 2-month period. The pathology showed numerous fungal hyphae present that were pauci-septate with various branched angles and variable hyphal thickness. Fungal cultures grew Rhizopus species and a universal fungal PCR detected the Rhizopus oryzae complex. Based on the clinicopathologic correlation, the diagnosis of cutaneous mucormycosis was made. Cutaneous mucormycosis is an aggressive fungal infection of the Mucorales family occurring after the inoculation of fungal spores in disrupted skin. It usually presents as a necrotic eschar but can also present as cellulitis that evolves into a necrotic ulcer. A prompt diagnosis is critical for the effective management of cutaneous mucormycosis. The treatment includes an immediate systemic treatment with amphotericin B and a surgical debridement of the necrotic regions. Given the wide range of presenting symptoms, clinical suspicion for this emergent condition must remain high in immunocompromised and diabetic patients. Full article

Background/Objectives: Vismia guianensis is a vegetal species popularly used to treat fungal infections. This study evaluated the anti-Candida effect of V. guianensis extract after C. albicans lethal infection in Tenebrio molitor larvae and mice. Methods and Results: The chemical profile analysis of a hydroethanolic extract of the leaves of V. guianensis (EHVG) identified 14 compounds. Two sets of experiments used T. molitor larvae. To evaluate toxicity, the uninfected larvae were treated with EHVG or anthraquinone. We considered the following groups: the controls received PBS; ANFO B received amphotericin B (600 mg/mL); EHVG received the extract; and ANTQ received anthraquinone. The extract and anthraquinone resulted in low-level toxicity in the T. molitor larvae. Another set of experiments evaluated the EHVG effect during lethal infection with Candida albicans. The T. molitor larvae were treated intracelomically (ic/10 μL). Treatment with EHVG efficiently improved the survival of the larvae after lethal infection (60%), probably due to the reduction in CFUs. In the mice, the antifungal effect of EHVG was determined in three groups of immunosuppressed Swiss mice (cyclophosphamide, 50 mg/kg/ip) infected with C. albicans (1 × 10⁷ CFU/ip). The control animals were infected and untreated; the ANFO B animals were infected and treated with amphotericin B (600 µg/kg/ip); and the EHVG animals were infected and treated with the extract (5 mg/kg/orally). A SHAM group (uninfected and untreated) was also included. Survival was assessed for 5 days. The extract increased the mice’s survival (60%) and life expectancy, reducing the CFU counts in the peritoneum and blood. EHVG also increased the number of blood neutrophils and peritoneal macrophages. These systemic activities are likely associated with the presence of flavonoids in the extract. Conclusions: The beneficial effects of EHVG in lethal sepsis are related to an antifungal effect, with the number of CFUs decreasing in the larvae and the mice. In addition, EHVG showed immunological activity in the mice, considering immune cell distribution and cytokine production. Full article

Aspergillus flavus is a medically relevant fungus, particularly in tropical regions. Although its aflatoxin production and thermotolerance are well documented, its biofilm-forming ability has received less attention, despite being a key factor in the virulence of A. flavus as an opportunistic pathogen, which can significantly impact therapeutic outcomes. To investigate the influence of temperature on the growth and biofilm formation of an A. flavus isolate, we compared it on solid media with the reference strain A. flavus ATCC 22546 and documented morphological changes during conidial germination. We examined biofilm formation in both strains across different temperatures and evaluated the susceptibility of this A. flavus isolate to antifungal agents in both planktonic and biofilm form. Our results showed that the temperature can promote conidiation on solid media. Radial growth was highest at 28 °C, while the conidial count and density were favored at higher temperatures. Moreover, we determined that 37 °C was the optimal temperature for conidial germination and biofilm formation. We described four distinct phases in A. flavus biofilm development—initiation (0–12 h), consolidation (12–24 h), maturation (24–48 h), and dispersion (48–72 h)—with the notable presence of conidial heads at 42 °C. Carbohydrates and proteins constitute the primary components of the extracellular matrix. We observed an abundance of lipid droplets within the hyphae of the MMe18 strain biofilm. The mature biofilms demonstrated reduced susceptibility to amphotericin B and itraconazole, requiring higher inhibitory concentrations for both antifungals compared with their planktonic counterparts. Full article

Candida auris is an emerging multidrug-resistant fungal pathogen causing nosocomial transmission and invasive infections with high mortality. This study aimed to investigate the genetic relationships, enzymatic activities, and drug-resistance profiles of C. auris isolates to evaluate the population and epidemiological diversity of candidiasis in Russia. A total of 112 clinical isolates of C. auris were analyzed from May 2017 to March 2023 in 18 hospitals across Saint Petersburg, the Leningrad Region, and Moscow. Species identification was confirmed by ITS sequencing, and genotyping was performed using 12 short tandem repeat (STR) markers. Antifungal susceptibility was tested using Sensititre™ YeastOne™ plates, and hydrolytic enzyme production was measured by the plate method. ITS sequencing confirmed that all isolates belonged to a single ITS cluster (clades I and III). Fifteen distinct STR genotypes were identified, with genotype I being dominant (n = 53). The most variable of the analyzed markers turned out to be M3-Ia, which was represented in the Russian population by eight different variants. Fluconazole resistance was found in 111 isolates, 17% were resistant to amphotericin B, and 3.6% to 5-flucytosine. Phospholipase activity was strong in most strains, especially in urine isolates (p = 0.014). Conclusion: The predominance of STR genotype I and its variability at the M3-Ia locus suggest its association with nosocomial outbreaks and transmissibility in Russia. Full article

Leishmaniasis, a neglected tropical disease caused by Leishmania species, presents serious public health challenges due to limited treatment options, toxicity, high costs, and drug resistance. In this study, the in vitro potential of malvidin and echioidinin is examined as antileishmanial agents against L. amazonensis, L. braziliensis, and L. infantum, comparing their effects to amphotericin B (AmpB), a standard drug. Malvidin demonstrated greater potency than echioidinin across all parasite stages and species. Against L. amazonensis, malvidin’s IC₅₀ values were 197.71 ± 17.20 µM (stationary amastigotes) and 258.07 ± 17 µM (axenic amastigotes), compared to echioidinin’s 272.99 ± 29.90 μM and 335.96 ± 19.35 μM. AmpB was more potent, with IC₅₀ values of 0.06 ± 0.01 µM and 0.10 ± 0.03 µM. Malvidin exhibited lower cytotoxicity (CC₅₀: 2920.31 ± 80.29 µM) than AmpB (1.06 ± 0.12 µM) and a favorable selectivity index. It reduced infection rates by 35.75% in L. amazonensis-infected macrophages. The in silico analysis revealed strong binding between malvidin and Leishmania arginase, with the residues HIS139 and PRO258 playing key roles. Gene expression analysis indicated malvidin’s modulation of oxidative stress and DNA repair pathways, involving genes like GLO1 and APEX1. These findings suggest malvidin’s potential as a safe, natural antileishmanial compound, warranting further in vivo studies to confirm its therapeutic efficacy and pharmacokinetics in animal models. Full article