RESUMO
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list (FPPL). This systematic review aimed to evaluate the epidemiology and impact of invasive fungal disease due to Mucorales. PubMed and Web of Science were searched to identify studies published between January 1, 2011 and February 23, 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 24 studies were included. Mortality rates of up to 80% were reported. Antifungal susceptibility varied across agents and species, with the minimum inhibitory concentrations lowest for amphotericin B and posaconazole. Diabetes mellitus was a common risk factor, detected in 65%-85% of patients with mucormycosis, particularly in those with rhino-orbital disease (86.9%). Break-through infection was detected in 13.6%-100% on azole or echinocandin antifungal prophylaxis. The reported prevalence rates were variable, with some studies reporting stable rates in the USA of 0.094-0.117/10 000 discharges between 2011 and 2014, whereas others reported an increase in Iran from 16.8% to 24% between 2011 and 2015. Carefully designed global surveillance studies, linking laboratory and clinical data, are required to develop clinical breakpoints to guide antifungal therapy and determine accurate estimates of complications and sequelae, annual incidence, trends, and global distribution. These data will provide robust estimates of disease burden to refine interventions and better inform future FPPL.
Assuntos
Antifúngicos , Mucorales , Mucormicose , Organização Mundial da Saúde , Humanos , Mucorales/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Mucormicose/epidemiologia , Mucormicose/microbiologia , Mucormicose/tratamento farmacológico , Mucormicose/mortalidade , Fatores de Risco , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/prevenção & controle , Infecções Fúngicas Invasivas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Prevalência , Farmacorresistência Fúngica , Incidência , Saúde Global/estatística & dados numéricosRESUMO
Aim: Currently, we have limited armamentarium of antifungal agents against Mucorales. There is an urgent need to discover novel antifungal agents that are effective, safe and affordable. Materials & methods: In this study, the anti-Mucorale action of native lactoferrin (LF) and its functional fragments CLF, RR6 and LFcin against three common Mucorale species are reported. The synergistic action of LF with antifungal agents like amphotericin B, isavuconazole and posaconazole was analyzed using checkerboard technique. Results: All the three mucor species showed inhibition when treated with fragments. The checkerboard assay confirmed that native LF showed the best synergistic action against Mucorales in combination with Amphotericin B. Conclusion: These results highlight the potential therapeutic value of native LF against Mucorales.
Black fungus, or 'mucormycosis', is a dangerous fungal infection. Normally, it affects people with a weakened immune system. It is only treatable when diagnosed early. It spreads by breathing the fungus in, eating contaminated food or direct contact with an infected wound. There are not many medicines that can treat this type of fungus, so it is important to find new ones. In this study, we tested a natural protein called lactoferrin and some of its building blocks, called peptides, to see if they could stop the fungus from growing. Lactoferrin and its peptides could stop the fungus from growing, especially when used with a medicine called amphotericin B. This means that lactoferrin could potentially be a helpful treatment for this fungal infection.
Assuntos
Anfotericina B , Antifúngicos , Sinergismo Farmacológico , Lactoferrina , Testes de Sensibilidade Microbiana , Mucormicose , Lactoferrina/farmacologia , Lactoferrina/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Mucormicose/tratamento farmacológico , Mucormicose/microbiologia , Anfotericina B/farmacologia , Humanos , Triazóis/farmacologia , Triazóis/uso terapêutico , Mucorales/efeitos dos fármacos , Mucor/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêuticoRESUMO
BACKGROUND: A strain of Phycomyces blakesleeanus (Mucorales, Mucoromycota) that was previously isolated after ultraviolet mutagenesis has altered responses to polyene antifungal drugs, sterol profiles, and phototropism of its sporangia. In this study, the genetic basis for these changes was sought. METHODS AND RESULTS: Two base pair substitutions were identified in the mutant within a P. blakelesleeanus gene that is homologous to others characterized from fungi, such as the Saccharomyces cerevisiae ERG3 gene, encoding sterol Δ5,6-desaturase. The polyene resistance and growth reduction phenotypes co-segregated with mutations in the gene in genetic crosses. The P. blakelesleeanus wild type ergC gene complemented a S. cerevisiae deletion strain of ERG3. CONCLUSIONS: This gene discovery may contribute towards better antifungal use in treating mucormycoses diseases caused by related species in the order Mucorales.
Assuntos
Farmacorresistência Fúngica/genética , Phycomyces/efeitos dos fármacos , Phycomyces/genética , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Genes Fúngicos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mucorales/efeitos dos fármacos , Mucorales/genética , Oxirredutases/genética , Preparações Farmacêuticas , Phycomyces/metabolismo , Polienos , Saccharomyces cerevisiae/genéticaAssuntos
Antifúngicos/uso terapêutico , COVID-19/complicações , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Infecções Oculares Fúngicas/tratamento farmacológico , Mucorales/efeitos dos fármacos , Mucormicose/tratamento farmacológico , Doenças Nasais/tratamento farmacológico , Doenças Orbitárias/tratamento farmacológico , Antifúngicos/efeitos adversos , COVID-19/imunologia , COVID-19/virologia , Infecções Fúngicas do Sistema Nervoso Central/imunologia , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Infecções Oculares Fúngicas/imunologia , Infecções Oculares Fúngicas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Mucorales/imunologia , Mucorales/patogenicidade , Mucormicose/imunologia , Mucormicose/microbiologia , Doenças Nasais/imunologia , Doenças Nasais/microbiologia , Doenças Orbitárias/imunologia , Doenças Orbitárias/microbiologia , Fatores de Risco , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Resultado do TratamentoRESUMO
The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from N-substituted 4-piperidone derivatives by reductive amination with appropriate amines using sodium triacetoxyborohydride. Antifungal activity was determined on the model strain Yarrowia lipolytica, and some compounds showed interesting growth-inhibiting activity. These compounds were tested on 20 clinically relevant fungal isolates (Aspergillus spp., Candida spp., Mucormycetes) by standardized microbroth dilution assays. Two of the six compounds, 1-benzyl-N-dodecylpiperidin-4-amine and N-dodecyl-1-phenethylpiperidin-4-amine, were identified as promising candidates for further development based on their in vitro antifungal activity against Candida spp. and Aspergillus spp. Antifungal activity was determined for 18 Aspergillus spp. and 19 Candida spp., and their impact on ergosterol and cholesterol biosynthesis was determined. Toxicity was determined on HL-60, HUVEC, and MCF10A cells, and in the alternative in vivo model Galleria mellonella. Analysis of sterol patterns after incubation gave valuable insights into the putative molecular mechanism of action, indicating inhibition of the enzymes sterol C14-reductase and sterol C8-isomerase in fungal ergosterol biosynthesis.
Assuntos
Antifúngicos/farmacologia , Ergosterol/metabolismo , Fungos/efeitos dos fármacos , Piperidinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus/efeitos dos fármacos , Aspergillus/metabolismo , Vias Biossintéticas/efeitos dos fármacos , Candida/efeitos dos fármacos , Candida/metabolismo , Descoberta de Drogas , Fungos/metabolismo , Humanos , Mucorales/efeitos dos fármacos , Mucorales/metabolismo , Micoses/tratamento farmacológico , Micoses/metabolismo , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
Mucormycosis is a deadly infection which is caused by fungi of the order Mucorales including species belonging to the genus Rhizopus, Mucor, Mycocladus, Rhizomucor, Cunninghamella, and Apophysomyces. Despite antifungal therapy and surgical procedures, the mortality rate of this disease is about 90-100% which is exceptionally high. The hypersensitivity of patients with raised available serum iron indicates that the Mucorales are able to use host iron as a critical factor of virulence. This is because iron happens to be a crucial element playing its role in the growth of cells and development. In this review, we have described Lactoferrin (Lf) as a potential iron-chelator. Lf is a naturally occurring glycoprotein which is expressed in most of the biological fluids. Moreover, Lf possesses exclusive anti-inflammatory effects along with several anti-fungal effects that could prove to be helpful to the pathological physiology of inexorable mucormycosis cases. This literature summarises the biological insights into the Lf being considered as a potential fungistatic agent and an immune regulator. The review also proposes that unique potential of Lf as an iron-chelator can be exploited as the adjunct treatment for mucormycosis infection.
Assuntos
Antifúngicos/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Lactoferrina/uso terapêutico , Mucorales/efeitos dos fármacos , Mucormicose/tratamento farmacológico , Animais , Antifúngicos/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Quelantes de Ferro/efeitos adversos , Lactoferrina/efeitos adversos , Mucorales/metabolismo , Mucorales/patogenicidade , Mucormicose/diagnóstico , Mucormicose/metabolismo , Mucormicose/microbiologia , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). The new compounds were assessed as cytotoxic candidates against human breast cancer cells (MCF-7) and hepatocellular carcinoma cells (HepG-2). All the new compounds appeared as more potent cytotoxic agents than erlotinib, while only compound 4a exhibited more potency than 5-flourouracil and 4b analogue was equipotent to it. Accordingly, the kinase suppression effect of 4a and 4b was further evaluated against EGFRWT, EGFRL858R and EGFRT790M. Both pyrimidine analogues 4a and 4b displayed outstanding inhibitory activity against EGFRWT and its two mutated isoforms EGFRL858R and EGFRT790M in comparing to erlotinib and osimertinib as reference drugs. Additionally, all the new analogues were subjected to antimicrobial assay. Interestingly, both 4a and 4b represented the most promising activity of wide spectrum antimicrobial effect against the examined microbes in comparison to gentamycin and ketoconazole as standard drugs. Moreover, docking results proved the good binding interactions of the compounds 4a and 4b with EGFRWT and EGFRT790M which were in accordance with the results of the in vitro enzyme assay. Additional in silico ADMET studies were performed for the new derivatives which represented their good oral absorption, good drug-likeness properties and low toxicity risks in human.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus fumigatus/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mucorales/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteus vulgaris/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Streptococcus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To study the possible association between invasive fungal sinusitis (mucormycosis) and coronavirus disease. METHODS: A prospective observational study was conducted at a tertiary care centre over four months, involving all patients with mucormycosis of the paranasal sinuses suffering from or having a history of coronavirus disease infection. RESULTS: Twenty-three patients presented with mucormycosis, all had an association with coronavirus disease 2019. The ethmoids (100 per cent) were the most common sinuses affected. Intra-orbital extension was seen in 43.47 per cent of cases, while intracranial extension was only seen in 8.69 per cent. Diabetes mellitus was present in 21 of 23 cases, and was uncontrolled in 12 cases. All patients had a history of steroid use during their coronavirus treatment. CONCLUSION: New manifestations of coronavirus disease 2019 are appearing over time. The association between coronavirus and mucormycosis of the paranasal sinuses must be given serious consideration. Uncontrolled diabetes and over-zealous use of steroids are two main factors aggravating the illness, and both of these must be properly checked.
Assuntos
COVID-19/microbiologia , Mucorales/isolamento & purificação , Mucormicose/microbiologia , Seios Paranasais/microbiologia , Administração Intravenosa , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/virologia , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Índia/epidemiologia , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/microbiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mucorales/efeitos dos fármacos , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Mucormicose/etiologia , Pandemias , Seios Paranasais/diagnóstico por imagem , Estudos Prospectivos , SARS-CoV-2 , Sinusite/diagnóstico , Sinusite/microbiologia , Esteroides/efeitos adversos , Esteroides/uso terapêuticoRESUMO
BACKGROUND: Mucorales are opportunistic pathogens that can cause life-threatening diseases predominantly in immunocompromised patients. OBJECTIVES: This study aimed to investigate the frequency, seasonal variation and antifungal susceptibility of pathogenic Mucorales in the soil collected from seven hospitals in Urmia, Iran, between November 2017 and July 2018 in four different seasons. METHODS: Mucorales isolates obtained from soil were characterised based on conventional and molecular assays. In addition, in vitro antifungal susceptibility was performed using the CLSI M38Ed3 procedure. RESULTS: Out of 196 tested soil samples, 80 (40.8%) samples were positive for mucoralean fungi. Rhizopus arrhizus var. arrhizus (n = 47) was the most frequent species followed by Mucor circinelloides (n = 21) and Cunninghamella echinulata (n = 6). A seasonal variation in the frequency of Mucorales in soil was detected with a maximum of culture-positive soil samples detected in wet autumn (43.2%) followed by winter (23.4%), summer (19.7%) and spring (13.6%). In vitro antifungal susceptibility testing for 80 environmental isolates exhibited MIC of ≤2 µg/ml for amphotericin B indicating the smallest range of MIC variation among the tested Mucorales (range: 0.125-2 µg/ml). Among the azoles, posaconazole was the most effective antifungals (GM MIC, 0.724 µg/ml). CONCLUSIONS: We considered associations of species and seasonal frequencies between soil mucoralean fungi and mucormycosis. The effect of opportunistic Mucorales dominating in the soil and prevalent causative agents of mucormycosis in Iran reported in the literatures but more comprehensive studies are needed to confirm this conclusion.
Assuntos
Mucorales , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Cunninghamella/efeitos dos fármacos , Cunninghamella/isolamento & purificação , Hospitais , Humanos , Irã (Geográfico) , Testes de Sensibilidade Microbiana , Mucor/efeitos dos fármacos , Mucor/isolamento & purificação , Mucorales/efeitos dos fármacos , Mucorales/isolamento & purificação , Mucormicose/transmissão , Infecções Oportunistas/transmissão , Rhizopus/efeitos dos fármacos , Rhizopus/isolamento & purificação , Estações do Ano , Solo , Microbiologia do Solo , Triazóis/farmacologiaRESUMO
Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies describing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonaute proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases (RdRP) and an atypical ribonuclease III (RNase III). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.
Assuntos
Farmacorresistência Fúngica , Mucorales/patogenicidade , Interferência de RNA , Antifúngicos/farmacologia , Mucorales/efeitos dos fármacos , Mucorales/genética , Estabilidade de RNA , RNA Fúngico/genética , RNA Mensageiro/química , Transdução de SinaisRESUMO
Rhizomes of Zingiber neesanum (Graham) Ramamoorthy, endemic to Western Ghats and subject to few studies, were analysed for bioactivity and phytochemical composition. High total tannin (TT) content in isopropanol extract [55.261 ± 6.623 mg TAE.100 g-1 DW] contributed to antimicrobial activity against gram negative Enterococcus fecalis (21.7 ± 0.6 cm) while high total flavonoid (TF) content in ethyl acetate extract [681.94 ± 33.87 mg CE.100 g-1 DW] accounted for the antifungal activity against Mucor rouxii (9.7 ± 0.6). Isopropanol extracts also showed high anti-oxidant activity as determined by DPPH and FRAP assays. Major bioactive phytochemical constituents in Z. neesanum rhizome identified by GC-MS analysis included 2-Methyl-7-nonadecene (13.99%; antimicrobial), Actinomycin C2 (8.57%; antineoplastic) and Deoxyspergualin (12.55%; immunosuppressive).
Assuntos
Anti-Infecciosos , Antioxidantes , Polifenóis/farmacologia , Zingiberaceae/química , Anti-Infecciosos/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Índia , Mucorales/efeitos dos fármacos , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Polifenóis/isolamento & purificação , Rizoma/químicaRESUMO
Mucormycosis is an invasive, life-threatening fungal infection that mainly affects immunocompromised hosts. We collected data of pediatric mucormycosis cases from all 7 Greek Hematology-Oncology Departments for the years 2008-2017. Six cases of invasive mucormycosis diagnosed during treatment for malignancies were included in the study. In 4 children (66%) mucormycosis occurred within the first 20 days after diagnosis of the underlying disease. Two cases were classified as proven mucormycosis and 4 as probable. The most frequently recorded species was Rhizopus arrhizus (2 patients), followed by Mucor spp (1), and Lichtheimia spp (1). All patients received liposomal amphotericin B. Combined antifungal treatment was used in 5 cases. Surgical excision was performed in 4 cases (66%). Two patients died at 6 and 12 months after the diagnosis, respectively, 1 (17%) because of mucormycosis. Our data suggest that mucormycosis may occur early after the initiation of intensive chemotherapy in children with malignancies.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Neoplasias Hematológicas/complicações , Mucormicose/complicações , Mucormicose/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/imunologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Mucor/efeitos dos fármacos , Mucor/imunologia , Mucor/isolamento & purificação , Mucorales/efeitos dos fármacos , Mucorales/imunologia , Mucorales/isolamento & purificação , Mucormicose/imunologia , Rhizopus oryzae/efeitos dos fármacos , Rhizopus oryzae/imunologia , Rhizopus oryzae/isolamento & purificaçãoRESUMO
Alveolar macrophages (AM) are the first-line lung defense against Mucorales in pulmonary mucormycosis. Since corticosteroid use is a known risk factor for mucormycosis, the aim of this study was to describe the role of corticosteroids on AM capacities to control Lichtheimia corymbifera spore growth using a new ex vivo model. An in vivo mouse model was developed to determine the acetate cortisone dose able to trigger pulmonary invasive infection. Then, in the ex vivo model, male BALB/c mice were pretreated with the corticosteroid regimen triggering invasive infection, before AM collection through bronchoalveolar lavage. AMs from corticosteroid-treated mice and untreated control AMs were then exposed to L. corymbifera spores in vitro (ratio 1:5). AM control of fungal growth, adherence/phagocytosis, and oxidative burst were assessed using optical densities by spectrophotometer, flow cytometry, and 2', 7'-dichlorofluoresceine diacetate fluorescence, respectively. Cortisone acetate at 500 mg/kg, at D-3 and at D0, led to pulmonary invasive infection at D3. Co-incubated spores and AMs from corticosteroid-treated mice had significantly higher absorbance (fungal growth) than co-incubated spores and control AMs, at 24 h (P = .025), 36 h (P = .004), and 48 h (P = .001). Colocalization of spores with AMs from corticosteroid-treated mice was significantly lower than for control AMs (7.6 ± 1.9% vs 22.3 ± 5.8%; P = .003), reflecting spore adherence and phagocytosis inhibition. Finally, oxidative burst was significantly increased when control AMs were incubated with spores (P = 0.029), while corticosteroids hampered oxidative burst from treated AMs (P = 0.321). Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease in our ex vivo model. LAY SUMMARY: The aim of this study was to describe the impact of corticosteroids on alveolar macrophage (AM) capacities to control Mucorales growth in a new murine ex vivo model. Corticosteroids enhanced fungal growth of L. corymbifera through AM phagocytosis inhibition and burst oxidative decrease.
Assuntos
Corticosteroides/administração & dosagem , Pulmão/microbiologia , Macrófagos Alveolares/efeitos dos fármacos , Mucorales/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Esporos Fúngicos/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucorales/crescimento & desenvolvimento , Mucormicose/imunologia , Mucormicose/microbiologiaRESUMO
BACKGROUND: It has been reported that the genes coding for NADP-dependent glutamate dehydrogenases (NADP-GDHs) showed a cause-effect relationship with Yeast-Hypha (YH) reversible transition in a zygomycete Benjaminiella poitrasii. As YH transition is significant in human pathogenic fungi for their survival and proliferation in the host, the NADP-GDHs can be explored as antifungal drug targets. METHODS: The yeast-form specific BpNADPGDH I and hyphal-form specific BpNADPGDH II of B. poitrasii were purified by heterologous expression in E. coli BL-21 cells and characterized. The structural analogs of L-glutamate, dimethyl esters of isophthalic acid (DMIP) and its derivatives were designed, synthesized and screened for inhibition of NADP-GDH activity as well as YH transition in B. poitrasii, and also in human pathogenic Candida albicans strains. RESULTS: The BpNADPGDH I and BpNADPGDH II were found to be homo-hexameric proteins with native molecular mass of 282 kDa and 298 kDa, respectively and subunit molecular weights of 47 kDa and 49 kDa, respectively. Besides the distinct kinetic properties, BpNADPGDH I and BpNADPGDH II were found to be regulated by cAMP-dependent- and Calmodulin (CaM) dependent- protein kinases, respectively. The DMIP compounds showed a more pronounced effect on H-form specific BpNADPGDH II and inhibited YH transition as well as growth in B. poitrasii and C. albicans strains. CONCLUSION: The present study will be useful to design and develop antifungal drugs against dimorphic human pathogens using glutamate dehydrogenase as a target. SIGNIFICANCE: Glutamate dehydrogenases can be explored as a target against human pathogenic fungi.
Assuntos
Antifúngicos/farmacologia , Inibidores Enzimáticos/farmacologia , Desidrogenase de Glutamato (NADP+)/antagonistas & inibidores , Desidrogenase de Glutamato (NADP+)/metabolismo , Mucorales/enzimologia , Animais , Antifúngicos/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Desidrogenase de Glutamato (NADP+)/isolamento & purificação , Humanos , Mucorales/química , Mucorales/efeitos dos fármacos , Mucorales/metabolismo , Mucormicose/tratamento farmacológico , Mucormicose/microbiologia , Fosforilação/efeitos dos fármacos , OvinosRESUMO
BACKGROUND: Lichtheimia species are emerging opportunistic fungal pathogens in the Mucorales, causing serious skin and respiratory infections in immunocompromised patients. Established agents are Lichtheimia corymbifera and L. ramosa, while L. ornata is a novel agent. Available data on a species-specific analysis of Lichtheimia infections are limited. METHODS: The first case of a fatal rhino-orbital-cerebral infection in a hematopoietic stem cell transplantation recipient caused by L. ornata is reported; the agent was identified by sequencing the ITS ribosomal region. We reviewed the literature on mucormycosis due to Lichtheimia species between 2009 and 2018, with an analysis of risk factors and epidemiological and clinical data. RESULTS: In addition to our Lichtheimia ornata case, 44 cases of human Lichtheimia were analyzed. Lichtheimia predominated in Europe (68.2%), followed by Asia (16%), and Africa (9%). The most common underlying condition was hematological malignancy (36.3%), followed by trauma/major surgery (27.3%), while diabetes mellitus was rare (11.4%). Site of infection was mostly skin and soft tissues (45.5%) and lung (25%), while relatively few cases were disseminated (13.6%) or rhinocerebral (11.4%). Mortality (36.4%) was mainly due to disseminated and rhinocerebral infections. CONCLUSION: In contrast to Rhizopus, the most common agent of mucormycosis recorded in patients with diabetes mellitus, Lichtheimia infections were primarily associated with hematological malignancies and major skin barrier damage. Given the fact that classical rhinocerebral mucormycosis remains difficult to treat, independent of causative species, timely application of amphotericin B accessory to debridement may be required for patient survival.
Assuntos
Hospedeiro Imunocomprometido , Mucorales/patogenicidade , Mucormicose/microbiologia , Adulto , Anemia Aplástica/complicações , Olho/microbiologia , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Testes de Sensibilidade Microbiana , Mucorales/classificação , Mucorales/efeitos dos fármacos , Mucorales/isolamento & purificação , Cavidade Nasal/microbiologia , Infecções Oportunistas/microbiologia , FilogeniaRESUMO
Blakeslea trispora is a natural source of carotenoids, including ß-carotene and lycopene, which have industrial applications. Therefore, classical selective breeding techniques have been applied to generate strains with increased productivity, and microencapsulated ß-carotene preparation has been used in food industry (Li et al., 2019). In B. trispora, lycopene is synthesized via the mevalonate pathway (Venkateshwaran et al., 2015). Lycopene cyclase, which is one of the key enzymes in this pathway, is a bifunctional enzyme that can catalyze the cyclization of lycopene to produce ß-carotene and exhibit phytoene synthase activity (He et al., 2017).
Assuntos
Fermentação , Cromatografia Gasosa-Espectrometria de Massas/métodos , Mucorales/efeitos dos fármacos , Nicotina/farmacologia , beta Caroteno/biossíntese , Ciclo do Ácido Cítrico , Licopeno/metabolismo , Mucorales/metabolismoRESUMO
The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis.
Assuntos
Genes Fúngicos , Interações Hospedeiro-Patógeno , Mucorales/genética , Farmacorresistência Fúngica , Redes e Vias Metabólicas , Mucorales/efeitos dos fármacos , Mucorales/metabolismo , Mucorales/patogenicidadeRESUMO
Mycenarubinâ C, a previously unknown red pyrroloquinoline alkaloid, was isolated from fruiting bodies of the mushroom Mycena rosea and its structure was elucidated mainly by NMR spectroscopy and mass spectrometry. Unlike mycenarubinâ A, the major pyrroloquinoline alkaloid in fruiting bodies of M.â rosea, mycenarubinâ C, contains an eight-membered ring with an additional C1 unit that is hitherto unprecedented for pyrroloquinoline alkaloids known in nature. Incubation of mycenarubinâ A with an excess of formaldehyde revealed that mycenarubinâ C was generated nearly quantitatively from mycenarubinâ A. An investigation into the formaldehyde content of fresh fruiting bodies of M.â rosea showed the presence of considerable amounts of formaldehyde, with values of 5â µg per gram of fresh weight in fresh fruiting bodies. Although mycenarubinâ C did not show bioactivity against selected bacteria and fungi, formaldehyde inhibits the growth of the mycoparasite Spinellus fusiger at concentrations present in fruiting bodies of M.â rosea. Therefore, formaldehyde might play an ecological role in the chemical defence of M.â rosea against S.â fusiger. In turn, S.â fusiger produces gallic acid-presumably to detoxify formaldehyde by reaction of this aldehyde with amino acids and gallic acid to Mannich adducts.
Assuntos
Agaricales/química , Alcaloides/farmacologia , Formaldeído/farmacologia , Carpóforos/química , Mucorales/efeitos dos fármacos , Pirróis/farmacologia , Quinolinas/farmacologia , Agaricales/imunologia , Agaricales/metabolismo , Alcaloides/biossíntese , Aminoácidos/metabolismo , Antibiose , Formaldeído/metabolismo , Carpóforos/imunologia , Carpóforos/metabolismo , Ácido Gálico/metabolismo , Inativação Metabólica/fisiologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mucorales/metabolismo , Pirróis/metabolismo , Quinolinas/metabolismoRESUMO
BACKGROUND: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability. OBJECTIVES: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment. METHODS: We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction). RESULTS: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (nâ=â4/5) of patients receiving 1st-POSnew, for 27.8% (nâ=â5/18) receiving 1st-AMB+POSnew and for 50.0% (nâ=â11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (nâ=â1/5) in 1st-POSnew versus 53.3% (nâ=â8/15) in 1st-AMB; 33.3% (nâ=â6/18) in 1st-AMB+POSnew versus 52.0% (nâ=â26/50) in 1st-AMB; and 0.0% (nâ=â0/22) in SAL-POSnew versus 4.4% (nâ=â2/45) in SAL-POSsusp]. CONCLUSIONS: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.
Assuntos
Antifúngicos/administração & dosagem , Infecções Fúngicas Invasivas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Triazóis/administração & dosagem , Adolescente , Adulto , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/química , Criança , Pré-Escolar , Composição de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Mucorales/efeitos dos fármacos , Mucormicose/sangue , Estudos Prospectivos , Sistema de Registros , Triazóis/química , Adulto JovemRESUMO
MIC values for amphotericin B and three azoles determined by the EUCAST reference technique and by gradient concentration strips were compared for 30 Mucorales isolates belonging to clinically important species. Essential agreement (EA) within ±2 dilution steps at 24 hours between the techniques was 83.3% for isavuconazole. EAs for itraconazole, amphotericin B, and posaconazole were 86.7%, 73.3%, and 56.7%, respectively. A good agreement was obtained between visual and spectrophotometric readings for EUCAST.