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2.
Indian J Ophthalmol ; 69(4): 987-989, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33727474

RESUMO

A 42-year-old male patient presented with profound impairment of vision in both eyes, just as he was recovering from COVID-19. A known diabetic and hypertensive, he suffered from COVID-19 pneumonia further complicated by ARDS, septicaemia and acute kidney injury. His vision on presentation was finger counting close to face bilaterally with multiple, yellowish lesions at the posterior pole. Based on the clinical findings and previous blood culture report, it was diagnosed as candida retinitis and treated with oral and intravitreal anti-fungals. The lesions were regressing at follow-up. This is a post COVID-19 presumed candida retinitis case report.


Assuntos
/diagnóstico , Candidíase/diagnóstico , Infecções Oculares Fúngicas/diagnóstico , Infecções Oportunistas/diagnóstico , Retinite/diagnóstico , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Fluconazol/uso terapêutico , Humanos , Injeções Intravítreas , Masculino , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia , Retinite/tratamento farmacológico , Retinite/microbiologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Voriconazol/uso terapêutico
3.
Eur J Med Chem ; 216: 113337, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33713977

RESUMO

A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.


Assuntos
Inibidores de 14-alfa Desmetilase/química , Antifúngicos/química , Miconazol/química , Selênio/química , Esterol 14-Desmetilase/química , Inibidores de 14-alfa Desmetilase/metabolismo , Inibidores de 14-alfa Desmetilase/farmacologia , Inibidores de 14-alfa Desmetilase/uso terapêutico , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Sítios de Ligação , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Candida/fisiologia , Candidíase/tratamento farmacológico , Candidíase/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Miconazol/metabolismo , Miconazol/farmacologia , Miconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade
4.
Int J Nanomedicine ; 16: 119-132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33447031

RESUMO

Purpose: This manuscript aimed at encapsulating an antifungal terconazole (TCZ) into innovative novasomes for improving its penetration into the skin and clinically modulating its therapeutic efficacy. Methods: Novasomes containing free fatty acid (FFA) as a penetration enhancer were formulated using ethanol injection technique based on 24 full factorial design to explore the impact of various formulation variables on novasomes characteristics regarding entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). The optimum formulation was chosen using Design-Expert® software and utilized for further explorations. Results: The chosen formulation (N15; including 100 mg lipid components and Span 80 to oleic acid in a ratio of 2:1 (w/w)) exhibited an EE% = 99.45 ± 0.78%, PS = 623.00 ± 2.97 nm, PDI = 0.40 ± 0.04, and ZP = -73.85 ± 0.64 mV. N15 showed spherical vesicles with a higher deformability index (DI) (9.62 ± 0.15 g) compared to traditional niosomal formulation (0.92 ± 0.12 g). Further, N15 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis-(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition tests revealed a superior TCZ deposition inside the skin from N15 in comparison to traditional niosomal formulation and TCZ suspension. Furthermore, histopathological examination for rats assured the safety of N15 for topical use. A clinical study conducted on infants suffering from napkin candidiasis proved the superiority of N15 to placebo in providing a complete cure of such fungal infections. Conclusion: Concisely, the obtained outcomes confirmed the pronounced efficacy of N15 to successfully treat skin fungal infections.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Triazóis/administração & dosagem , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Análise Fatorial , Humanos , Lactente , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Eletricidade Estática , Suspensões , Triazóis/farmacologia , Triazóis/uso terapêutico
5.
J Med Chem ; 64(2): 1116-1126, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33356256

RESUMO

Due to the evolution and development of antifungal drug resistance, limited efficacy of existing drugs has led to high mortality in patients with serious fungal infections. To develop novel antifungal therapeutic strategies, herein a series of carboline fungal histone deacetylase (HDAC) inhibitors were designed and synthesized, which had potent synergistic effects with fluconazole against resistant Candida albicans infection. In particular, compound D12 showed excellent in vitro and in vivo synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of C. albicans by blocking morphological mutual transformation and inhibiting biofilm formation. Mechanism studies revealed that the reversion of drug resistance was due to downregulation of the expression of the azole target gene ERG11 and efflux gene CDR1. Taken together, fungal HDAC inhibitor D12 offered a promising lead compound for combinational treatment of azole-resistant candidiasis.


Assuntos
Azóis/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Carbolinas/síntese química , Carbolinas/uso terapêutico , Farmacorresistência Fúngica/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Biofilmes/efeitos dos fármacos , Candida albicans/enzimologia , Candidíase/microbiologia , Carbolinas/toxicidade , Quimioterapia Combinada , Feminino , Fluconazol/farmacologia , Proteínas Fúngicas/efeitos dos fármacos , Fungos/efeitos dos fármacos , Fungos/enzimologia , Inibidores de Histona Desacetilases/toxicidade , Humanos , Fígado/patologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
6.
Biomed Pharmacother ; 133: 111043, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378951

RESUMO

Nosocomial Candida colonization causes Systemic candidiasis in human with invasive infections in immunocompromised patients. Of all Candida spp., C. albicans is dominant in morbidity of all systemic candidiasis but C. tropicalis is phenomenal in mortality, virulence aspects and resistance development against antifungal drugs. The present study investigated the synergistic anti-virulent activity of myristic acid (MA) and palmitic acid (PA) against insidious dimorphic Candida spp. (C. albicans and C. tropicalis). In vitro and qPCR results revealed the mechanisms of MA-PA combination effectively inhibiting various virulence aspects such as biofilm, hyphal formation, secreted aspartyl proteases, lipases, ergosterol biosynthesis and drug effluxes. Further, in Danio rerio (Zebrafish), the MA-PA treatment increased the survival of animals and also the treated groups showed decreased level of fungal burden compared to the infected controls, after 3rd day of post infection. Histopathology of vital organs and SEM analysis of skin revealed a drastic recovery and reduced the inflammation of both Candida spp. infections in MA-PA treated animals. In addition, MA-PA treatment reduced the haemolysin and increased the susceptibility of Candida spp. in human blood model. Hence, this study suggested the therapeutic utilization of MA-PA as synergistic combination for their anti-inflammatory potency against systemic candidiasis and candidemia.


Assuntos
Anti-Inflamatórios/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Candidíase/tratamento farmacológico , Ácido Mirístico/farmacologia , Ácido Palmítico/farmacologia , Animais , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Candida tropicalis/crescimento & desenvolvimento , Candida tropicalis/patogenicidade , Candidíase/microbiologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Viabilidade Microbiana , Virulência , Peixe-Zebra
7.
BMC Infect Dis ; 20(1): 827, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176724

RESUMO

BACKGROUND: Candida auris is a new pathogen called "superbug fungus" which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic review and meta-analysis was undertaken to determine the epidemic situation, drug resistance patterns and mortality of C. auris. METHODS: We systematically searched studies on the clinical report of Candida auris in Pubmed, Embase and Cochrane databases until October 6, 2019. A standardized form was used for data collection, and then statics was performed with STATA11.0. RESULTS: It showed that more than 4733 cases of C. auris were reported in over 33 countries, with more cases in South Africa, United States of America, India, Spain, United Kingdom, South Korea, Colombia and Pakistan. C. auirs exhibited a decrease in case count after 2016. Clade I and III were the most prevalent clades with more cases reported and wider geographical distribution. Blood stream infection was observed in 32% of the cases, which varied depending on the clades. Resistance to fluconazole, amphotericin B, caspofungin, micafungin and anidulafungin in C. auris were 91, 12, 12.1, 0.8 and 1.1%. The overall mortality of C. auris infection was 39%. Furthermore, subgroup analyses showed that mortality was higher in bloodstream infections (45%), and lower in Europe (20%). CONCLUSIONS: Over 4000 cases of C. auris were reported in at least 33 countries, which showed high resistance to fluconazole, moderate resistance to amphotericin B and caspofungin, high sensitivity to micafungin and anidulafungin. The crude mortality for BSI of C. auris was 45% which was similar to some drug-resistant bacteria previously reported. In conclusion, C. auris displayed similar characteristics to some drug resistance organisms. This study depicts several issues of C. auris that are most concerned, and is of great significance for the clinical management.


Assuntos
Candida/efeitos dos fármacos , Candidíase/epidemiologia , Candidíase/mortalidade , Anfotericina B/uso terapêutico , Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Candida/classificação , Candida/genética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Caspofungina/uso terapêutico , Farmacorresistência Fúngica Múltipla/efeitos dos fármacos , Fluconazol/uso terapêutico , Humanos , Micafungina/uso terapêutico , Prevalência
8.
BMC Infect Dis ; 20(1): 739, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032533

RESUMO

BACKGROUND: Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions. CASE PRESENTATION: We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention. CONCLUSIONS: In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.


Assuntos
Candida/efeitos dos fármacos , Candidíase/imunologia , Hospedeiro Imunocomprometido , Espondilite/tratamento farmacológico , Espondilite/imunologia , Idoso , Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Candidemia/induzido quimicamente , Candidemia/tratamento farmacológico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Candidíase/cirurgia , Humanos , Quimioterapia de Indução/efeitos adversos , Masculino , Micafungina/uso terapêutico , Espondilite/microbiologia , Espondilite/cirurgia , Resultado do Tratamento , Voriconazol/uso terapêutico
9.
PLoS One ; 15(9): e0238428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941438

RESUMO

OBJECTIVES: Recurrent vulvovaginal candidiasis (RVVC) causes significant morbidity. Candida albicans is the main pathogen associated with both sporadic and recurrent candidiasis. Due to unsatisfactory treatment effect, the impact of chlorhexidine digluconate and fluconazole alone or in combination on C. albicans and biofilm was investigated. METHODS: Vaginal C. albicans isolates from 18 patients with recurrent candidiasis and commensals from 19 asymptomatic women were isolated by culture. Crystal violet, XTT and colony forming unit assay were used to analyze the effect of chlorhexidine digluconate and fluconazole on growth of C. albicans, formation of new and already established, mature, biofilm. RESULTS: Fluconazole reduced the growth of planktonic C. albicans. However, in established biofilm, fluconazole had no effect on the candida cells and was not able to disperse and reduce the biofilm. By contrast, chlorhexidine digluconate had a direct killing effect on C. albicans grown both planktonically and in biofilm. Chlorhexidine digluconate also dispersed mature biofilm and inhibited formation of new biofilm. No major differences were observed between commensal isolates and candida causing recurrent vulvovaginitis with respect to biofilm or growth after chlorhexidine digluconate treatment. CONCLUSION: Biofilm is a problem in patients with recurrent vulvovaginal candidiasis reducing the effect of antifungal treatment. Development of new treatment strategies are urgently needed to decrease the recurrences. In already established biofilm, chlorhexidine digluconate dispersed the biofilm and was more effective in eradicating candida compared to fluconazole. Future treatment strategy may thus be a combination of chlorhexidine digluconate and fluconazole and prophylactic use of chlorhexidine digluconate to prevent biofilm formation and restrict infections.


Assuntos
Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Clorexidina/análogos & derivados , Adulto , Antifúngicos/farmacologia , Biofilmes/crescimento & desenvolvimento , Candida/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/microbiologia , Clorexidina/metabolismo , Clorexidina/farmacologia , Feminino , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana/métodos , Vagina/microbiologia
10.
PLoS Genet ; 16(8): e1009005, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841236

RESUMO

Azole drugs are the most frequently used antifungal agents. The pathogenic yeast Candida glabrata acquires resistance to azole drugs via single amino acid substitution mutations eliciting a gain-of-function (GOF) hyperactive phenotype in the Pdr1 transcription factor. These GOF mutants constitutively drive high transcription of target genes such as the ATP-binding cassette transporter-encoding CDR1 locus. Previous characterization of Pdr1 has demonstrated that this factor is negatively controlled by the action of a central regulatory domain (CRD) of ~700 amino acids, in which GOF mutations are often found. Our earlier experiments demonstrated that a Pdr1 derivative in which the CRD was deleted gave rise to a transcriptional regulator that could not be maintained as the sole copy of PDR1 in the cell owing to its toxically high activity. Using a set of GOF PDR1 alleles from azole-resistant clinical isolates, we have analyzed the mechanisms acting to repress Pdr1 transcriptional activity. Our data support the view that Pdr1-dependent transactivation is mediated by a complex network of transcriptional coactivators interacting with the extreme C-terminal part of Pdr1. These coactivators include but are not limited to the Mediator component Med15A. Activity of this C-terminal domain is controlled by the CRD and requires multiple regions across the C-terminus for normal function. We also provide genetic evidence for an element within the transactivation domain that mediates the interaction of Pdr1 with coactivators on one hand while restricting Pdr1 activity on the other hand. These data indicate that GOF mutations in PDR1 block nonidentical negative inputs that would otherwise restrain Pdr1 transcriptional activation. The strong C-terminal transactivation domain of Pdr1 uses multiple different protein regions to recruit coactivators.


Assuntos
Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Antifúngicos/efeitos adversos , Antifúngicos/farmacologia , Azóis/efeitos adversos , Azóis/farmacologia , Candida glabrata/genética , Candida glabrata/patogenicidade , Candidíase/genética , Candidíase/microbiologia , Proteínas de Ligação a DNA , Farmacorresistência Fúngica/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Ativação Transcricional/efeitos dos fármacos
12.
J Laryngol Otol ; 134(7): 592-596, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32713390

RESUMO

BACKGROUND: Fungal otitis externa is prevalent in tropical and sub-tropical climates; however, over the past two decades, there has been a reported increase in the prevalence of otomycosis in paediatric patients from more temperate climates. This study aimed to review the children diagnosed with otomycosis at the University Hospital Limerick with reference to frequency, causative organism, predisposing factors and management. METHODS: A retrospective review was conducted of paediatric patients from 2001 to 2015. Patients with positive fungal ear swabs and a diagnosis of otomycosis were identified. RESULTS: Ninety-three patients were positive for candida (mean age, 5.8 years), 10 patients were positive for aspergillus (mean age, 9.1 years) and 1 patient had mixed fungal infection containing both fungi. There was a positive correlation between a diagnosis of otomycosis and prior treatment with topical fluoroquinolones (r = 0.8; p < 0.01). CONCLUSION: The incidence of otomycosis has been increasing since 2001, which correlates with an increase in the use of topical fluoroquinolones. Previous studies identify aspergillus as the commonest causative fungi; however, this study found that candida was the commonest isolated fungi in the paediatric population.


Assuntos
Otomicose/epidemiologia , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Aspergilose/microbiologia , Candidíase/diagnóstico , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Candidíase/microbiologia , Criança , Pré-Escolar , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Coinfecção/epidemiologia , Coinfecção/microbiologia , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Masculino , Otomicose/diagnóstico , Otomicose/tratamento farmacológico , Otomicose/microbiologia , Estudos Retrospectivos
13.
J Mycol Med ; 30(3): 101011, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32693980

RESUMO

INTRODUCTION: Otomycosis, a superficial fungal infection of the external auditory canal (EAC), is a disease with exceptionally high prevalence. AIM: The aim of this study was to determine the prevalence of otomycosis, the distribution of causative species and to evaluate epidemiological characteristics of these infections. METHODOLOGY: The patients' data were collected from record book and database of mycological examinations conducted at Public Health Institute Nis, Serbia. In the period from 2014 to 2018 samples of 1287 patients with symptoms and signs of EAC infection were investigated. Standard mycological methods were used for isolation and determination of fungi. RESULTS: High prevalence of otomycosis was determined in examined patients (22.7%). However, the prevalence rates did not differ significantly in the studied period (p=0.931). The majority of patients were diagnosed with only unilateral EAC infection (82.9%). Considering all patients with otomycosis, mold infections caused by the genus Aspergillus (143/48.9%) were more frequent than Candida spp. ear infections (133/45.6%), with Aspergillus niger and Candida аlbicans being predominant causative agents. Mixed Aspergillus and Candida otomycosis was established in 16 (5.5%) patients. Otomycosis was more common in male subjects (26.8%, p=0.003) who also suffered from Aspergillus otomycosis more frequently (17.5%, p<0.001). The prevalence of these infections increases with age (p=0.005), while they do not show seasonal pattern (p>0.05). CONCLUSION: Noted high prevalence of otomycosis, with both yeasts and non-dermatophyte molds acting as infectious agents which require different treatment, implies the necessity for further epidemiological monitoring of this form of superficial mycoses.


Assuntos
Otomicose/epidemiologia , Otomicose/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/classificação , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Aspergilose/microbiologia , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/isolamento & purificação , Candida/classificação , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Candidíase/microbiologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Técnicas de Tipagem Micológica , Otomicose/tratamento farmacológico , Prevalência , Sérvia/epidemiologia , Adulto Jovem
14.
PLoS One ; 15(7): e0235746, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678853

RESUMO

Azole resistant fungal infections remain a health problem for the immune compromised. Current therapies are limited due to rises in new resistance mechanisms. Therefore, it is important to identify new drug targets for drug discovery and novel therapeutics. Arv1 (are1 are2 required for viability 1) function is highly conserved between multiple pathogenic fungal species. Candida albicans (C. albicans) cells lacking CaArv1 are azole hypersusceptible and lack virulence. Saccharomyces cerevisiae (S. cerevisiae) Scarv1 cells are also azole hypersusceptible, a phenotype reversed by expression of CaArv1, indicating conservation in the molecular mechanism for azole susceptibility. To define the relationship between Arv1 function and azole susceptibility, we undertook a structure/function analysis of ScArv1. We identified several conserved amino acids within the ScArv1 homology domain (ScAhd) required for maintaining normal azole susceptibility. Erg11 lanosterol 14-α-demethylase is the rate-limiting enzyme in sterol biosynthesis and is the direct target of azole antifungals, so we used our ScArv1 mutants in order to explore the relationship between ScArv1 and ScErg11. Specific ScArv1 mutants ectopically expressed from a low copy plasmid were unable to restore normal azole susceptibility to Scarv1 cells and had reduced Erg11 protein levels. Erg11 protein stability depended on its ability to form a heterodimeric complex with Arv1. Complex formation was required for maintaining normal azole susceptibility. Scarv1 cells expressing orthologous CaArv1 mutants also had reduced CaErg11 levels, were unable to form a CaArv1-CaErg11 complex, and were azole hypersusceptible. Scarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 could not sustain proper levels of the azole resistant CaErg11Y132F F145L protein. Caarv1/Caarv1 cells expressing CaArv1 mutants unable to interact with CaErg11 were found to lack virulence using a disseminated candidiasis mouse model. Expressing CaErg11Y132F F145L did not reverse the lack of virulence. We hypothesize that the role of Arv1 in Erg11-dependent azole resistance is to stabilize Erg11 protein level. Arv1 inhibition may represent an avenue for treating azole resistance.


Assuntos
Candida albicans/patogenicidade , Candidíase/microbiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Esterol 14-Desmetilase/metabolismo , Virulência , Sequência de Aminoácidos , Animais , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/genética , Farmacorresistência Fúngica , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência , Esterol 14-Desmetilase/genética
15.
BMC Infect Dis ; 20(1): 438, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571233

RESUMO

BACKGROUND: Candida sp. osteoarticular infection is rare and most often due to hematogenous seeding during an episode of candidemia in immunocompromised patients. However, the diagnosis can be delayed in patients with subtle symptoms and signs of joint infection without a concurrent episode of candidemia. CASE PRESENTATION: A 75-year-old woman presented with a three-year history of pain and swelling of the left knee. Candida pelliculosa was detected from the intraoperative tissue when the patient had undergone left total knee arthroplasty 32 months ago, but no antifungal treatment was performed. One year after the total knee arthroplasty, C. pelliculosa was repeatedly isolated from the left knee synovial fluid and antifungal treatment comprising amphotericin B deoxycholate and fluconazole was administered. However, joint infection had extended to the adjacent bone and led to progressive joint destruction. The patient underwent surgery for prosthesis removal and received prolonged antifungal treatment with micafungin and fluconazole. CONCLUSIONS: This case shows that C. pelliculosa, an extremely rare non-Candida albicans sp., can cause fungal arthritis and lead to irreversible joint destruction owing to delayed diagnosis and treatment.


Assuntos
Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/microbiologia , Candida/patogenicidade , Candidíase/microbiologia , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Artroplastia do Joelho/efeitos adversos , Candida/isolamento & purificação , Candidemia/tratamento farmacológico , Candidemia/etiologia , Candidíase/tratamento farmacológico , Ácido Desoxicólico/uso terapêutico , Remoção de Dispositivo , Combinação de Medicamentos , Feminino , Fluconazol/uso terapêutico , Humanos , Cuidados Intraoperatórios , Prótese Articular , Joelho/microbiologia , Joelho/cirurgia , Micafungina/uso terapêutico , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia
16.
Int J Nanomedicine ; 15: 3681-3693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547022

RESUMO

Background: Fungal infections are becoming more prevalent and threatening because of the continuous emergence of azole-resistant fungal infections. The present study was aimed to assess the activity of free Methylglyoxal (MG) or MG-conjugated chitosan nanoparticles (MGCN) against fluconazole-resistant Candida albicans. Materials and Methods: A novel formulation of MGCN was prepared and characterized to determine their size, shape and polydispersity index. Moreover, the efficacy of fluconazole or MG or MGCN was determined against intracellular C. albicans in macrophages and the systematic candidiasis in a murine model. The safety of MG or MGCN was tested in mice by analyzing the levels of hepatic and renal toxicity parameters. Results: Candida albicans did not respond to fluconazole, even at the highest dose of 20 mg/kg, whereas MG and MGCN effectively eliminated C. albicans from the macrophages and infected mice. Mice in the group treated with MGCN at a dose of 10 mg/kg exhibited a 90% survival rate and showed the lowest fungal load in the kidney, whereas the mice treated with free MG at the same dose exhibited 50% survival rate. Moreover, the administration of MG or MGCN did not induce any liver and kidney toxicity in the treated mice. Conclusion: The findings of the present work suggest that MGCN may be proved a promising therapeutic formulation to treat azole-resistant C. albicans infections.


Assuntos
Candidíase/tratamento farmacológico , Quitosana/química , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Nanopartículas/química , Aldeído Pirúvico/uso terapêutico , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candidíase/microbiologia , Modelos Animais de Doenças , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Fluconazol/farmacologia , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Tamanho da Partícula , Aldeído Pirúvico/farmacologia
19.
J Mycol Med ; 30(3): 100968, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32386800

RESUMO

OBJECTIVE: Candida parapsilosis species complex, an important set of non-albicans Candida species, is known to cause candidaemia particularly in neonates and infants. However, the incidence has increased in recent years, owing to higher numbers of at individuals at risk for these infections. Our objective was to evaluate the in vitro susceptibility of clinical isolates of C. parapsilosis complex isolates from Iran to seven antifungal drugs. MATERIAL AND METHODS: One hundred-one clinical isolates of C. parapsilosis species complex cultured from humans were included. Species identification had been previously confirmed by combined phenotypic characteristics, matrix-assisted laser desorption ionization-time of flight mass spectrometry-based assay and reconfirmed by DNA sequence analysis of the ITS rDNA region and D1/D2 gene. Minimum inhibitory concentrations (MICs) for amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, micafungin and anidulafungin were determined against well-characterized isolates by broth microdilution susceptibility testing according to the CLSI M27-A3 guideline. RESULTS: Species identifications were performed on 101 isolates, of which 88 (87.2%) C. parapsilosis sensu stricto and 13 (12.8%) C. orthopsilosis. Amphotericin B and posaconazole were the most active drugs with 100% of isolates being wild-type (WT). Voriconazole and micafungin, 99% of isolates were WT. The low activity was recorded for fluconazole and itraconazole with 93.1% and 89.1% of isolates being WT, respectively. At the species level, all Candida parapsilosis sensu stricto isolates were WT to amphotericin B and posaconazole and all Candida orthopsilosis isolates were WT to amphotericin B, voriconazole, posaconazole, anidulafungin and micafungin. In contrast, the highest rate of non-WT was observed in C. orthopsilosis to itraconazole (4 of 13, 30.8%). CONCLUSIONS: Although almost all of the tested drugs demonstrated potent activity against C. parapsilosis species complex, it seems that more especially C. orthopsilosis isolates had decreased susceptibility to itraconazole. Further studies are needed to determine how these findings may switch into in vivo efficacy.


Assuntos
Antifúngicos/farmacologia , Candida parapsilosis/efeitos dos fármacos , Candidíase/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Candida parapsilosis/crescimento & desenvolvimento , Candida parapsilosis/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Criança , Pré-Escolar , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Humanos , Lactente , Recém-Nascido , Irã (Geográfico)/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adulto Jovem
20.
PLoS Pathog ; 16(5): e1008478, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437438

RESUMO

Successful human colonizers such as Candida pathogens have evolved distinct strategies to survive and proliferate within the human host. These include sophisticated mechanisms to evade immune surveillance and adapt to constantly changing host microenvironments where nutrient limitation, pH fluctuations, oxygen deprivation, changes in temperature, or exposure to oxidative, nitrosative, and cationic stresses may occur. Here, we review the current knowledge and recent findings highlighting the remarkable ability of medically important Candida species to overcome a broad range of host-imposed constraints and how this directly affects their physiology and pathogenicity. We also consider the impact of these adaptation mechanisms on immune recognition, biofilm formation, and antifungal drug resistance, as these pathogens often exploit specific host constraints to establish a successful infection. Recent studies of adaptive responses to physiological niches have improved our understanding of the mechanisms established by fungal pathogens to evade the immune system and colonize the host, which may facilitate the design of innovative diagnostic tests and therapeutic approaches for Candida infections.


Assuntos
Adaptação Fisiológica/imunologia , Antifúngicos/uso terapêutico , Candida/fisiologia , Candidíase , Farmacorresistência Fúngica/imunologia , Interações Hospedeiro-Parasita/imunologia , Candidíase/tratamento farmacológico , Candidíase/imunologia , Candidíase/patologia , Humanos
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