RESUMO
Introduction. Sporotrichosis is a subcutaneous infection caused by dimorphic Sporothrix species embedded in the clinical clade. Fungi have virulence factors, such as biofilm and melanin production, which contribute to their survival and are related to the increase in the number of cases of therapeutic failure, making it necessary to search for new options.Gap statement. Proton pump inhibitors (PPIs) have already been shown to inhibit the growth and melanogenesis of other fungi.Aim. Therefore, this study aimed to evaluate the effect of the PPIs omeprazole (OMP), rabeprazole (RBP), esomeprazole, pantoprazole and lansoprazole on the susceptibility and melanogenesis of Sporothrix species, and their interactions with itraconazole, terbinafine and amphotericin B.Methodology. The antifungal activity of PPIs was evaluated using the microdilution method, and the combination of PPIs with itraconazole, terbinafine and amphotericin B was assessed using the checkerboard method. The assessment of melanogenesis inhibition was assessed using grey scale.Results. The OMP and RBP showed significant MIC results ranging from 32 to 256 µg ml-1 and 32 to 128 µg ml-1, respectively. Biofilms were sensitive, with a significant reduction (P<0.05) in metabolic activity of 52% for OMP and 50% for RBP at a concentration of 512 µg ml-1 and of biomass by 53% for OMP and 51% for RBP at concentrations of 512 µg ml-1. As for the inhibition of melanogenesis, only OMP showed inhibition, with a 54% reduction.Conclusion. It concludes that the PPIs OMP and RBP have antifungal activity in vitro against planktonic cells and biofilms of Sporothrix species and that, in addition, OMP can inhibit the melanization process in Sporothrix species.
Assuntos
Anfotericina B , Antifúngicos , Melanogênese , Inibidores da Bomba de Prótons , Sporothrix , Esporotricose , Humanos , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Itraconazol/farmacologia , Melaninas/biossíntese , Melaninas/metabolismo , Melanogênese/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Sporothrix/efeitos dos fármacos , Sporothrix/metabolismo , Esporotricose/tratamento farmacológico , Esporotricose/microbiologia , Terbinafina/farmacologiaRESUMO
BACKGROUND: Mycotic keratitis (MK) represents a corneal infection, with Fusarium species identified as the leading cause. Fusarium is a genus of filamentous fungi commonly found in soil and plants. While many Fusarium species are harmless, some can cause serious infections in humans and animals, particularly Fusarium keratitis, that can lead to severe ocular infections, prevalent cause of monocular blindness in tropical and subtropical regions of the world. Due to its incidence and importance in ophthalmology, we conducted a systematic analysis of clinical cases to increase our understanding of Fusarium keratitis by gathering clinical and demographic data. METHODS: To conduct an analysis of Fusarium keratitis, we looked through the literature from the databases PubMed, Embase, Lilacs, and Google Scholar and found 99 papers that, between March 1969 and September 2023, corresponded to 163 cases of Fusarium keratitis. RESULTS: Our analysis revealed the Fusarium solani species complex as the predominant isolate, with females disproportionately affected by Fusarium keratitis. Notably, contact lens usage emerged as a significant risk factor, implicated in nearly half of cases. Diagnosis primarily relied on culture, while treatment predominantly involved topical natamycin, amphotericin B, and/or voriconazole. Surprisingly, our findings demonstrated a prevalence of cases originating from the United States, suggesting potential underreporting and underestimation of this mycosis in tropical regions. This shows the imperative for heightened vigilance, particularly in underdeveloped regions with substantial agricultural activity, where Fusarium infections may be more prevalent than currently reported. CONCLUSION: Our study sheds light on the clinical complexities of Fusarium keratitis and emphasizes the need for further research and surveillance to effectively tackle this vision-threatening condition. Furthermore, a timely identification and early initiation of antifungal treatment appear to be as important as the choice of initial treatment itself.
Assuntos
Antifúngicos , Fusariose , Fusarium , Ceratite , Humanos , Ceratite/microbiologia , Ceratite/epidemiologia , Ceratite/tratamento farmacológico , Fusarium/isolamento & purificação , Fusarium/classificação , Fusarium/genética , Fusariose/microbiologia , Fusariose/tratamento farmacológico , Fusariose/epidemiologia , Fusariose/diagnóstico , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Infecções Oculares Fúngicas/microbiologia , Infecções Oculares Fúngicas/epidemiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Feminino , Voriconazol/uso terapêutico , Prevalência , Fatores de Risco , Masculino , Adulto , Pessoa de Meia-Idade , Lentes de Contato/microbiologia , Lentes de Contato/efeitos adversos , Anfotericina B/uso terapêutico , Natamicina/uso terapêutico , Idoso , Adulto Jovem , AdolescenteRESUMO
Mucormycosis is a rare fungal infection caused by fungi of the Mucorales order that occurs in immunocompromised individuals or with loss of skin or mucosa barrier integrity. This report presents four cases of rhinocerebral mucormycosis attended at a third-level hospital in Cali (Colombia) during a period of three years. All patients had different case histories and times of evolution. All four had a previous or de novo diagnosis of type 2 diabetes mellitus, with glycated hemoglobin higher than 10% on admission. We ruled out other possible pathologies that could explain their immunocompromised condition. Mucormycosis diagnosis was made with direct visualization of hyaline coenocytic hyphae on biopsies. The basis of treatment was liposomal amphotericin B and surgical debridement. Two patients presented bacterial coinfection. One asked for voluntary discharge without having completed the treatment, and another one died. The remaining two have attended controls and had an adequate evolution.
La mucormicosis es una infección fúngica poco frecuente causada por hongos del orden Mucorales, la cual se presenta en individuos inmunocomprometidos o con pérdida de la integridad de la barrera de piel o mucosas. Se reportan cuatro casos de mucormicosis rinocerebral atendidos en un hospital de tercer nivel de Cali (Colombia) durante un periodo de tres años. Los cuatro pacientes presentaron diferentes cuadros clínicos y tiempos de evolución. Todos tenían diagnóstico de diabetes mellitus de tipo 2, de novo o previo, con una hemoglobina glucosilada de ingreso mayor del 10 % y en todos se descartaron otras enfermedades que explicaran su compromiso inmunitario. La mucormicosis se diagnosticó por la visualización directa de hifas hialinas sincitiales (coenocytic) en las biopsias tomadas. El pilar del tratamiento fue la anfotericina B liposómica junto con el desbridamiento quirúrgico. Dos pacientes presentaron coinfección bacteriana. De los cuatro, uno firmó su egreso voluntario sin completar el tratamiento y otro falleció. Los dos pacientes restantes han asistido a los controles y han mostrado una adecuada evolución.
Assuntos
Anfotericina B , Mucormicose , Humanos , Mucormicose/diagnóstico , Masculino , Pessoa de Meia-Idade , Anfotericina B/uso terapêutico , Feminino , Antifúngicos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Idoso , Desbridamento , Hospedeiro ImunocomprometidoRESUMO
Leishmaniases, caused by Leishmania parasites, are widespread and pose significant health risks globally. Visceral leishmaniasis (VL) is particularly prevalent in Brazil, with high morbidity and mortality rates. Traditional treatments, such as pentavalent antimonials, have limitations due to toxicity and resistance. Therefore, exploring new compounds like lectins is crucial. Concanavalin A (ConA) has shown promise in inhibiting Leishmania growth. This study aimed to evaluate its leishmanicidal effect on L. infantum promastigotes and understand its mechanism of action. In vitro tests demonstrated inhibition of promastigote growth when treated with ConA, with IC50 values ranging from 3 to 5 µM over 24-72 h. This study suggests that ConA interacts with L. infantum glycans. Additionally, ConA caused damage to the membrane integrity of parasites and induced ROS production, contributing to parasite death. Scanning electron microscopy confirmed morphological alterations in treated promastigotes. ConA combined with the amphotericin B (AmB) showed synergistic effects, reducing the required dose of AmB, and potentially mitigating its toxicity. ConA demonstrated no cytotoxic effects on macrophages, instead stimulating their proliferation. These findings reinforce that lectin exhibits promising leishmanicidal activity against L. infantum promastigotes, making ConA a potential candidate for leishmaniasis treatment.
Assuntos
Antiprotozoários , Canavalia , Concanavalina A , Leishmania infantum , Leishmania infantum/efeitos dos fármacos , Concanavalina A/farmacologia , Animais , Antiprotozoários/farmacologia , Antiprotozoários/química , Sementes/química , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Anfotericina B/farmacologia , Lectinas/farmacologia , Lectinas/química , Lectinas/metabolismo , Lectinas de Plantas/farmacologia , Lectinas de Plantas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/parasitologiaRESUMO
Fusarium oxysporum is a cross-kingdom pathogen that infects humans, animals, and plants. The primary concern regarding this genus revolves around its resistance profile to multiple classes of antifungals, particularly azoles. However, the resistance mechanism employed by Fusarium spp. is not fully understood, thus necessitating further studies to enhance our understanding and to guide future research towards identifying new drug targets. Here, we employed an untargeted proteomic approach to assess the differentially expressed proteins in a soil isolate of Fusarium oxysporum URM7401 cultivated in the presence of amphotericin B and fluconazole. In response to antifungals, URM7401 activated diverse interconnected pathways, such as proteins involved in oxidative stress response, proteolysis, and lipid metabolism. Efflux proteins, antioxidative enzymes and M35 metallopeptidase were highly expressed under amphotericin B exposure. Antioxidant proteins acting on toxic lipids, along with proteins involved in lipid metabolism, were expressed during fluconazole exposure. In summary, this work describes the protein profile of a resistant Fusarium oxysporum soil isolate exposed to medical antifungals, paving the way for further targeted research and discovering new drug targets.
Assuntos
Anfotericina B , Antifúngicos , Fluconazol , Proteínas Fúngicas , Fusarium , Proteômica , Microbiologia do Solo , Fusarium/efeitos dos fármacos , Fusarium/metabolismo , Fusarium/genética , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Fluconazol/farmacologia , Anfotericina B/farmacologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Farmacorresistência Fúngica , Testes de Sensibilidade Microbiana , Proteoma/análiseRESUMO
BACKGROUND: Candida vulturna is an emerging pathogen belonging to the Metshnikowiaceae family together with Candida auris and Candida haemulonii species complex. Some strains of this species were reported to be resistant to several antifungal agents. OBJECTIVES: This study aims to address identification difficulties, evaluate antiungal susceptibilities and explore the molecular mechanisms of azole resistance of Candida vulturna. METHODS: We studied five C. vulturna clinical strains isolated in three Colombian cities. Identification was performed by phenotypical, proteomic and molecular methods. Antifungal susceptibility testing was performed following CLSI protocol. Its ERG11 genes were sequenced and a substitution was encountered in azole resistant isolates. To confirm the role of this substitution in the resistance phenotype, Saccharomyces cerevisiae strains with a chimeric ERG11 gene were created. RESULTS: Discrepancies in identification methods are highlighted. Sequencing confirmed the identification as C. vulturna. Antifungal susceptibility varied among strains, with four strains exhibiting reduced susceptibility to azoles and amphotericin B. ERG11 sequencing showed a point mutation (producing a P135S substitution) that was associated with the azole-resistant phenotype. CONCLUSIONS: This study contributes to the understanding of C. vulturna's identification challenges, its susceptibility patterns, and sheds light on its molecular mechanisms of azole resistance.
Assuntos
Antifúngicos , Azóis , Candida , Candidíase , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Candida/genética , Candida/classificação , Candida/isolamento & purificação , Candidíase/microbiologia , Humanos , Farmacorresistência Fúngica Múltipla/genética , Colômbia , Anfotericina B/farmacologia , Farmacorresistência Fúngica/genética , Mutação Puntual , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Proteínas Fúngicas/genética , Análise de Sequência de DNA , Proteínas de Saccharomyces cerevisiaeRESUMO
Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans. BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans. BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis. IMPORTANCE: Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii. There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans. BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of C. neoformans, acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against C. neoformans. We propose BRI as a new antifungal agent against cryptococcosis.
Assuntos
Antifúngicos , Criptococose , Cryptococcus neoformans , Saccharomyces cerevisiae , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Animais , Camundongos , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Modelos Animais de Doenças , Macrófagos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Testes de Sensibilidade Microbiana , Caspofungina/farmacologia , Feminino , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Anfotericina B/farmacologiaRESUMO
In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L. amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L. amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.
Assuntos
Anfotericina B , Antiprotozoários , Resistência a Medicamentos , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Animais , Brasil , Pessoa de Meia-Idade , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Humanos , Masculino , Camundongos , Leishmania/efeitos dos fármacos , Leishmania/isolamento & purificação , Leishmania/classificação , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/isolamento & purificação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Testes de Sensibilidade Parasitária , Camundongos Endogâmicos BALB C , Leishmaniose Tegumentar Difusa/parasitologia , Leishmaniose Tegumentar Difusa/tratamento farmacológicoRESUMO
Histoplasmosis presents a substantial clinical challenge globally, with a particular prevalence in South America, especially among patients with concurrent Human Immunodeficiency Virus (HIV) infection. Despite itraconazole's established efficacy, investigating alternative therapeutic approaches remains imperative. This is the largest study in our region to date, assessing the effectiveness of the less explored posaconazole treatment. This observational study, conducted at Fundación Valle del Lili (FVL) from 2016 to 2022, encompassed adults with disseminated histoplasmosis. Patients (n = 31) were treated with liposomal amphotericin B as an initial treatment, followed by consolidation treatment with posaconazole or itraconazole. Patients with single-organ cases, those lacking microbiological diagnosis, those who received initial treatment with antifungals other than liposomal Amphotericin B and those with < 6 months follow-up were excluded (Figure 1). Analyses considered population characteristics, treatments, and outcomes. Patients (average age: 45.6; 58.1% female) had common comorbidities (HIV 38.7%, solid organ transplantation 29% and oncologic disease 12.9%). Lungs (48.4%) and lymph nodes (16.1%) were commonly affected. Biopsy (64.5%) was the primary diagnostic method. Initial treatment with liposomal amphotericin B (100%) was given for 14 days on average. Follow-up indicated 71% completion with 19.4% requiring treatment modifications. Notably, 70.9% completed a posaconazole consolidation regimen over 350 days on average. Drug interactions during consolidation (80.6%) were common. No relapses occurred, and three deaths unrelated to histoplasmosis were reported. Traditionally, itraconazole has been the prevalent initial treatment; however, in our cohort, 55.9% of patients received posaconazole as the primary option. Encouragingly, posaconazole showed favorable tolerance and infection resolution, suggesting its potential as an effective and well-tolerated alternative for consolidation treatment. This finding prompts further exploration of posaconazole, potentially leading to more effective patient care and better outcomes.
Histoplasmosis is a critical concern in South America, notably among human immunodeficiency virus patients, leading to high mortality rates. This study, the largest in our region, investigates the effectiveness of posaconazole as an alternative treatment to itraconazole. The results offer the potential for enhanced patient care and improved outcomes.
Assuntos
Anfotericina B , Antifúngicos , Histoplasmose , Itraconazol , Humanos , Histoplasmose/tratamento farmacológico , Histoplasmose/epidemiologia , Histoplasmose/diagnóstico , Masculino , Feminino , Antifúngicos/uso terapêutico , Pessoa de Meia-Idade , Colômbia/epidemiologia , Adulto , Anfotericina B/uso terapêutico , Itraconazol/uso terapêutico , Triazóis/uso terapêutico , Resultado do Tratamento , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Idoso , Histoplasma/isolamento & purificação , Histoplasma/efeitos dos fármacosRESUMO
Candida spp. can be found in the human microbiome. However, immunocompromised patients are likely to develop invasive Candida infections, with mortality rates higher than 50%. The discovery of C. auris, a species that rapidly acquire antifungal resistance, increased the concern about Candida infections. The limited number of antifungal agents and the high incidence of resistance to them make imperative the development of new antifungal drugs. ß-lapachone is a biological active naphthoquinone that displays antifungal activity against C. albicans and C. glabrata. The aim of this study was to evaluate if this substance affects C. auris growth and elucidate its mechanism of action. A fluconazole-resistant C. auris isolate was used in this study. The antifungal activity of ß-lapachone was determined through microbroth dilution assays, and its mechanism of action was evaluated using fluorescent probes. Interaction with fluconazole and amphotericin B was assessed by disk diffusion assay and checkerboard. ß-lapachone inhibited planktonic C. auris cell growth by 92.7%, biofilm formation by 84.9%, and decrease the metabolism of preformed biofilms by 87.1% at 100 µg/ml. At 100 µg/ml, reductions of 30% and 59% of Calcofluor White and Nile red fluorescences were observed, indicating that ß-lapachone affects cell wall chitin and neutral lipids content, respectively. Also, the ratio 590 nm/529 nm of JC-1 decreased 52%, showing that the compound affects mitochondria. No synergism was observed between ß-lapachone and fluconazole or amphotericin B. Data show that ß-lapachone may be a promising candidate to be used as monotherapy to treat C. auris resistant infections.