RESUMEN
BACKGROUND: Microsporum audouinii has resurged recently. Infections with the dermatophyte are difficult to treat, which raises the question if we treat M. audouinii infections with the most effective antifungal (AF) agent. OBJECTIVES: The aims of this study was to investigate an outbreak of tinea capitis (TC) in Denmark, address the challenges in outbreak management and to conduct two reviews regarding previous outbreaks and minimal inhibitory concentration (MIC). METHODS: We used Wood's light, culture, direct microscopy, and PCR for screening and antifungal susceptibility testing (AFST) for treatment optimization. We performed two reviews to explore M. audouinii outbreaks and MIC values using broth microdilution method. RESULTS: Of 73 screened individuals, 10 had confirmed M. audouinii infections. Clinical resistance to griseofulvin was observed in 4 (66%) cases. While previous outbreaks showed high griseofulvin efficacy, our study favoured terbinafine, fluconazole and itraconazole in our hard-to-treat cases. AFST guided the choice of AF. Through the literature search, we identified five M. audouinii outbreaks, where differences in management included the use of Wood's light and prophylactic topical AF therapy. Terbinafine MIC values from the literature ranged from 0.002 to 0.125 mg/L. CONCLUSION: Use of Wood's light and preventive measurements were important for limiting infection. The literature lacked MIC data for griseofulvin against M. audouinii, but indicated sensitivity for terbinafine. The clinical efficacy for M. audouinii treatment was contradictory favouring both terbinafine and griseofulvin. AFST could have a key role in the treatment of difficult cases, but lack of standardisation of AFST and MIC breakpoints limits its usefulness.
Asunto(s)
Antifúngicos , Brotes de Enfermedades , Farmacorresistencia Fúngica , Pruebas de Sensibilidad Microbiana , Microsporum , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Humanos , Microsporum/efectos de los fármacos , Masculino , Femenino , Dinamarca/epidemiología , Adulto , Niño , Terbinafina/farmacología , Terbinafina/uso terapéutico , Persona de Mediana Edad , Tiña del Cuero Cabelludo/tratamiento farmacológico , Tiña del Cuero Cabelludo/microbiología , Tiña del Cuero Cabelludo/epidemiología , Griseofulvina/farmacología , Griseofulvina/uso terapéutico , Preescolar , Adolescente , Adulto Joven , Tiña/tratamiento farmacológico , Tiña/microbiología , Tiña/epidemiología , Itraconazol/farmacología , Itraconazol/uso terapéutico , Anciano , Fluconazol/farmacología , Fluconazol/uso terapéuticoRESUMEN
The extensive and repeated application of chemical fungicides results in the rapid development of fungicide resistance. Novel antifungal pesticides are urgently required. Natural products have been considered precious sources of pesticides. It is necessary to discover antifungal pesticides by using natural products. Herein, 42 various griseofulvin derivatives were synthesized. Their antifungal activities were evaluated in vitro. Most of them showed good antifungal activity, especially 3d exhibited a very broad antifungal spectrum and the most significant activities against 7 phytopathogenic fungi. In vivo activity results suggested that 3d protected apples and tomatoes from serious infection by phytopathogenic fungi. These proved that 3d had the potential to be a natural product-derived antiphytopathogenic fungi agent. Furthermore, docking analysis suggested that tubulin might be one of the action sites of 3d. It is reasonable to believe that griseofulvin derivatives are worth further development for the discovery of new pesticides.
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Hongos , Fungicidas Industriales , Griseofulvina , Enfermedades de las Plantas , Griseofulvina/farmacología , Griseofulvina/química , Griseofulvina/síntesis química , Fungicidas Industriales/farmacología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Enfermedades de las Plantas/microbiología , Relación Estructura-Actividad , Hongos/efectos de los fármacos , Simulación del Acoplamiento Molecular , Solanum lycopersicum/microbiología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/químicaRESUMEN
In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts.
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Griseofulvina , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Griseofulvina/farmacología , Antibacterianos/farmacología , Desarrollo de MedicamentosRESUMEN
Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss in older adults. nAMD is treated with biologics targeting vascular endothelial growth factor; however, many patients do not respond to the current therapy. Here, a small molecule drug, griseofulvin (GRF), is used due to its inhibitory effect on ferrochelatase, an enzyme important for choroidal neovascularization (CNV). For local and sustained delivery to the eyes, GRF is encapsulated in microparticles based on poly(lactide-co-glycolide) (PLGA), a biodegradable polymer with a track record in long-acting formulations. The GRF-loaded PLGA microparticles (GRF MPs) are designed for intravitreal application, considering constraints in size, drug loading content, and drug release kinetics. Magnesium hydroxide is co-encapsulated to enable sustained GRF release over >30 days in phosphate-buffered saline with Tween 80. Incubated in cell culture medium over 30 days, the GRF MPs and the released drug show antiangiogenic effects in retinal endothelial cells. A single intravitreal injection of MPs containing 0.18 µg GRF releases the drug over 6 weeks in vivo to inhibit the progression of laser-induced CNV in mice with no abnormality in the fundus and retina. Intravitreally administered GRF MPs prove effective in preventing CNV, providing proof-of-concept toward a novel, cost-effective nAMD therapy.
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Neovascularización Coroidal , Griseofulvina , Ratones , Humanos , Animales , Anciano , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Griseofulvina/farmacología , Griseofulvina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/prevención & controlRESUMEN
BACKGROUND: The number of terbinafine-resistant Trichophyton indotineae is increasing in recent years while the treatment is still a matter to discuss. OBJECTIVES: To explore the best therapeutic approach, we present real-world treatment of T. indotineae infection by analysing publicly available data. METHODS: We have reviewed all published articles, mainly including case reports and case series, on the drug-resistant T. mentagrophytes complex by using the key search terms to search the databases. RESULTS: We enrolled 25 articles from 14 countries, including 203 times of treatment information for 113 patients. The cure rate of itraconazole 200 mg per day at the fourth, eighth and the twelfth week were 27.27%, 48.48% and 54.55%, respectively, which was significantly higher than terbinafine 250 mg per day (8.77%, 24.56% and 28.07%) and even 500 mg/d terbinafine. Griseofulvin 500-1000 mg for 2-6 months may be effective while fluconazole had no record of successful treatment. Voriconazole and ravuconazole had potential therapeutic efficacy. Topical therapy alone showed limited therapeutic efficacy, but the combination with oral antifungals can be alternative. CONCLUSION: Oral itraconazole 200 mg per day for 4-8 weeks was the most effective treatment out of these commonly used antifungal drugs, and can be prior selection.
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Itraconazol , Naftalenos , Tiña , Humanos , Itraconazol/farmacología , Terbinafina/uso terapéutico , Terbinafina/farmacología , Estudios Retrospectivos , Naftalenos/farmacología , Antifúngicos/farmacología , Trichophyton , Griseofulvina/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
The marine-derived fungal strains KMM 4718 and KMM 4747 isolated from sea urchin Scaphechinus mirabilis as a natural fungal complex were identified as Penicillium sajarovii and Aspergillus protuberus based on Internal Transcribed Spacer (ITS), partial ß-tubulin (BenA), and calmodulin (CaM) molecular markers as well as an ribosomal polymerase two, subunit two (RPB2) region for KMM 4747. From the ethyl acetate extract of the co-culture, two new polyketides, sajaroketides A (1) and B (2), together with (2'S)-7-hydroxy-2-(2'-hydroxypropyl)-5-methylchromone (3), altechromone A (4), norlichexanthone (5), griseoxanthone C (6), 1,3,5,6-tetrahydroxy-8-methylxanthone (7), griseofulvin (8), 6-O-desmethylgriseofulvin (9), dechlorogriseofulvin (10), and 5,6-dihydro-4-methyl-2H-pyran-2-one (11) were identified. The structures of the compounds were elucidated using spectroscopic analyses. The absolute configurations of the chiral centers of sajaroketides A and B were determined using time-dependent density functional theory (TDDFT)-based calculations of the Electronic Circular Dichroism (ECD) spectra. The inhibitory effects of these compounds on urease activity and the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans were observed. Sajaroketide A, altechromone A, and griseofulvin showed significant cardioprotective effects in an in vitro model of S. aureus-induced infectious myocarditis.
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Penicillium , Policétidos , Staphylococcus aureus , Estructura Molecular , Policétidos/química , Griseofulvina/farmacología , Hongos , Dicroismo CircularRESUMEN
Six griseofulvin analogues named penigriseofulvins A - F (1-6), including three undescribed compounds and three undescribed natural products, were isolated from the fungus Penicillium griseofulvum. Their structures and absolute configurations were determined by NMR spectroscopic analyses, HRESIMS, and X-ray diffraction experiments. All compounds were evaluated for their anti-inflammatory activity, of which compounds 1 and 4 showed potential anti-inflammatory effects in RAW264.7 macrophages and ulcerative colitis mice.
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Griseofulvina , Penicillium , Ratones , Animales , Griseofulvina/farmacología , Antiinflamatorios/farmacología , Penicillium/química , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Griseofulvin was considered an effective agent for cancer therapy in past decades. Although the negative effects of griseofulvin on microtubule stability are known, the exact target and mechanism of action in plants remain unclear. Here, we used trifluralin, a well-known herbicide targeting microtubules, as a reference and revealed the differences in root tip morphology, reactive oxygen species production (ROS), microtubule dynamics, and transcriptome analysis between Arabidopsis treated with griseofulvin and trifluralin to elucidate the mechanism of root growth inhibition by griseofulvin. Like trifluralin, griseofulvin inhibited root growth and caused significant swelling of the root tip due to cell death induced by ROS. However, the presence of griseofulvin and trifluralin caused cell swelling in the transition zone (TZ) and meristematic zone (MZ) of root tips, respectively. Further observations revealed that griseofulvin first destroyed cortical microtubules in the cells of the TZ and early elongation zone (EZ) and then gradually affected the cells of other zones. The first target of trifluralin is the microtubules in the root MZ cells. Transcriptome analysis showed that griseofulvin mainly affected the expression of microtubule-associated protein (MAP) genes rather than tubulin genes, whereas trifluralin significantly suppressed the expression of αß-tubulin genes. Finally, it was proposed that griseofulvin could first reduce the expression of MAP genes, meanwhile increasing the expression of auxin and ethylene-related genes to disrupt microtubule alignment in root tip TZ and early EZ cells, induce dramatic ROS production, and cause severe cell death, eventually leading to cell swelling in the corresponding zones and inhibition of root growth.
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Proteínas de Arabidopsis , Arabidopsis , Tubulina (Proteína)/metabolismo , Arabidopsis/metabolismo , Griseofulvina/farmacología , Griseofulvina/metabolismo , Trifluralina/metabolismo , Trifluralina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Microtúbulos/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Raíces de Plantas/metabolismoRESUMEN
Natural products are important sources for the discovery of new pesticides. Chemical synthesis and structural modification can lead to pesticides. Despite abundant research in fungicide discovery for crop protection, there is an emerging need for the development of novel antifungal agrochemicals. Herein, 39 diversified griseofulvin derivatives were effectively synthesized from the natural product griseofulvin by diversity-oriented synthesis through the reactions of demethylation, ammonolysis, methylation, nitration, acylation, reduction, and chlorination. Among them, 31 derivatives were novel. All structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HR-MS), and the antifungal activity was investigated against five phytopathogenic fungi. Compounds 5h and 5l had excellent activity against Botrytis cinerea (5h, IC50 = 17.29 ± 0.64 µg/mL) and Alternaria solani (5l, IC50 = 22.52 ± 0.79 µg/mL), respectively. Compound 9 exhibited the more promising activities against three target fungi, especially against Colletotrichum gloeosporioides (IC50 = 7.24 ± 0.66 µg/mL), which is obviously better than positive control hymexazol, thifluzamide, and parent compound griseofulvin. In addition, compound 10 showed significant and extensive activities against four target fungi Cytospora sp. (IC50 = 18.72 ± 0.35 µg/mL), C. gloeosporioides (IC50 = 31.39 ± 1.48 µg/mL), A. solani (IC50 = 40.82 ± 1.04 µg/mL), and Fusarium solani (IC50 = 36.81 ± 0.82 µg/mL). Unexpectedly, 11 and 12, the chlorinated products of compound 9, exhibited the most promising activity against C. gloeosporioides (IC50 = 4.48 ± 0.54 µg/mL for 11, 2.24 ± 0.76 µg/mL for 12). Furthermore, 12 showed remarkable activity against Cytospora sp. (IC50 = 5.85 ± 0.72 µg/mL). Additionally, in vivo antifungal activity against C. gloeosporioides, homology modeling, and docking analysis of 11, 12, and griseofulvin were conducted. All results indicated that 11 and 12 had potency as antifungal agents against C. gloeosporioides, and the modifications of the 2' and 4' positions of griseofulvin should be further explored for higher-activity lead compounds or potential agricultural fungicides.
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Ascomicetos , Productos Biológicos , Fungicidas Industriales , Antifúngicos/química , Griseofulvina/farmacología , Productos Biológicos/farmacología , Relación Estructura-Actividad , Hongos , Fungicidas Industriales/químicaRESUMEN
The search for novel therapeutic strategies to treat fungal diseases is of special importance nowadays given the emerging threat of drug resistance. Various particulate delivery systems are extensively being developing to enhance bioavailability, site-specific penetration, and therapeutic efficacy of antimycotics. Recently, we have designed a novel topical formulation for griseofulvin (Gf) drug, which is currently commercially available in oral dosage forms due to its limited skin permeation. The proposed formulation is based on vaterite carriers that enabled effective incorporation and ultrasonically assisted delivery of Gf to hair follicles improving its dermal bioavailability. Here, we evaluated the effect of ultrasound on the viability of murine fibroblasts co-incubated with either Gf-loaded carriers or a free form of Gf and investigated the influence of both forms on different subpopulations of murine blood cells. The study revealed no sufficient cyto- and hemotoxicity of the carriers, even at the highest investigated concentrations. We also conducted a series of in vivo experiments to assess their multi-dose dermal toxicity and antifungal efficiency. Visual and histological examinations of the skin in healthy rabbits showed no obvious adverse effects after US-assisted application of the Gf-loaded carriers. At the same time, investigation of therapeutic efficiency for the designed formulation in comparison with free Gf and isoconazole drugs in a guinea pig model of trichophytosis revealed that the vaterite-based form of Gf provided the most rapid and effective cure of infected animals together with the reduction in therapeutic procedure number. These findings pave the way to improving antifungal therapy of superficial mycoses and justifying further preclinical studies.
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Antifúngicos , Micosis , Ratones , Animales , Conejos , Cobayas , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Griseofulvina/farmacología , Griseofulvina/uso terapéutico , Carbonato de Calcio/metabolismo , Carbonato de Calcio/farmacología , Carbonato de Calcio/uso terapéutico , Piel/metabolismo , Micosis/tratamiento farmacológicoRESUMEN
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of griseofulvin and usnic acid sulfonamides were synthesized and tested as possible CA inhibitors. Since ß- and γ- classes are expressed in microorganisms in addition to the α- class, showing substantial structural differences to the human isoforms they are also interesting as new antiinfective targets with a different mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Griseofulvin and usnic acid sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX as well as ß- and γ-CAs from different bacterial and fungal strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the three γ-CAs and Malassezia globosa (MgCA) enzyme. Six compounds (1b-1d, 1h, 1i and 1j) were more potent than AAZ against hCA I while five (1d, 1h, 1i, 1j and 4a) showed better activity than AAZ against the hCA II isoform. Moreover, all compounds appeared to be very potent against MgCA with a Ki lower than that of the reference drug. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of human CAs.
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Inhibidores de Anhidrasa Carbónica , Griseofulvina , Humanos , Inhibidores de Anhidrasa Carbónica/química , Griseofulvina/farmacología , Relación Estructura-Actividad , Dióxido de Carbono , Isoenzimas/metabolismo , Sulfonamidas/química , Anhidrasa Carbónica IX/metabolismo , Estructura MolecularRESUMEN
Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Griseofulvina/farmacología , Griseofulvina/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/patología , Centrosoma , NucleotidiltransferasasRESUMEN
Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from -3.34 to -5.61 kcal mol-1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.
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COVID-19 , Policétidos , Ratones , Humanos , Ratas , Animales , Griseofulvina/farmacología , Antifúngicos/farmacología , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Simulación del Acoplamiento Molecular , Glicoproteína de la Espiga del Coronavirus , Queratinas/metabolismo , ARN Polimerasa Dependiente del ARNRESUMEN
Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for mosquito and liver stages. Despite having backup mechanisms to acquire hemoglobin-heme, pathway intermediates and/or enzymes from the host, asexual parasites express heme pathway enzymes and synthesize heme. Here we show heme synthesized in asexual stages promotes cerebral pathogenesis by enhancing hemozoin formation. Hemozoin is a parasite molecule associated with inflammation, aberrant host-immune responses, disease severity and cerebral pathogenesis. The heme pathway knockout parasites synthesize less hemozoin, and mice infected with knockout parasites are protected from cerebral malaria and death due to anemia is delayed. Biosynthetic heme regulates food vacuole integrity and the food vacuoles from knockout parasites are compromised in pH, lipid unsaturation and proteins, essential for hemozoin formation. Targeting parasite heme synthesis by griseofulvin-a FDA-approved antifungal drug, prevents cerebral malaria in mice and provides an adjunct therapeutic option for cerebral and severe malaria.
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Malaria Cerebral , Parásitos , Animales , Griseofulvina/farmacología , Hemo/metabolismo , Hemoglobinas , Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/prevención & control , Ratones , Parásitos/metabolismoRESUMEN
Treatment options for Coronavirus Disease 2019 (COVID-19) remain limited, and the option of repurposing approved drugs with promising medicinal properties is of increasing interest in therapeutic approaches to COVID-19. Using computational approaches, we examined griseofulvin and its derivatives against four key anti-SARS-CoV-2 targets: main protease, RdRp, spike protein receptor-binding domain (RBD), and human host angiotensin-converting enzyme 2 (ACE2). Molecular docking analysis revealed that griseofulvin (CID 441140) has the highest docking score (-6.8 kcal/mol) with main protease of SARS-CoV-2. Moreover, griseofulvin derivative M9 (CID 144564153) proved the most potent inhibitor with -9.49 kcal/mol, followed by A3 (CID 46844082) with -8.44 kcal/mol against M protease and ACE2, respectively. Additionally, H bond analysis revealed that compound A3 formed the highest number of hydrogen bonds, indicating the strongest inhibitory efficacy against ACE2. Further, molecular dynamics (MD) simulation analysis revealed that griseofulvin and these derivatives are structurally stable. These findings suggest that griseofulvin and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection.
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Tratamiento Farmacológico de COVID-19 , Enzima Convertidora de Angiotensina 2 , Antivirales/química , Antivirales/farmacología , Antivirales/uso terapéutico , Griseofulvina/farmacología , Griseofulvina/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
This study aimed to evaluate the effect of proteinase K on mature biofilms of dermatophytes, by assays of metabolic activity and biomass. In addition, the proteinase K-terbinafine and proteinase K-griseofulvin interactions against these biofilms were investigated by the checkerboard assay and scanning electron and confocal microscopy. The biofilms exposed to 32 µg ml-1 of proteinase K had lower metabolic activity and biomass, by 39% and 38%, respectively. Drug interactions were synergistic, with proteinase K reducing the minimum inhibitory concentration of antifungals against dermatophyte biofilms at a concentration of 32 µg ml-1 combined with 128-256 µg ml-1 of terbinafine and griseofulvin. Microscopic images showed a reduction in biofilms exposed to proteinase K, proteinase K-terbinafine and proteinase K-griseofulvin combinations. These findings demonstrate that proteinase K has activity against biofilms of dermatophytes, and the interactions of proteinase K with terbinafine and griseofulvin improve the activity of drugs against mature dermatophyte biofilms.
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Antifúngicos , Arthrodermataceae , Antifúngicos/farmacología , Biopelículas , Endopeptidasa K/farmacología , Griseofulvina/farmacología , Pruebas de Sensibilidad Microbiana , Terbinafina/farmacologíaRESUMEN
AIMS: According to the WHO, 20-25% of people worldwide are affected by skin infections caused by dermatophytes, such as those of the Trichophyton genus. Additionally, several dermatophytes have developed resistance to drugs such as griseofulvin and itraconazole. This study tested 2S albumins-derived antimicrobial peptides (AMPs) as alternative antidermatophytic molecules. MAIN METHODS: Membrane pore formation assays, tests to detect overproduction of ROS, scanning electron microscopy (SEM) and fluorescence microscopy (FM) were carried out to provide insight into the mechanisms of antidermatophytic action. KEY FINDINGS: All AMPs (at 50 µg mL-1) tested reduced the mycelial growth of T. mentagrophytes and T. rubrum by up to 95%. In contrast, using a concentration 20-fold higher, griseofulvin only inhibited T. mentagrophytes by 35%, while itraconazole was not active against both dermatophytes. Scanning electron and fluorescence microscopies revealed that the six AMPs caused severe damage to hyphal morphology by inducing cell wall rupture, hyphal content leakage, and death. Peptides also induced membrane pore formation and oxidative stress by overproduction of ROS. Based on the stronger activity of peptides than the commercial drugs and the mechanism of action, all six peptides have the potential to be either employed as models to develop new antidermatophytic drugs or as adjuvants to existing ones. SIGNIFICANCE: The synthetic peptides are more efficient than conventional drug to treat infection caused by dermatophytes being potential molecules to develop new drugs.
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Antifúngicos/farmacología , Arthrodermataceae/efectos de los fármacos , Griseofulvina/farmacología , Itraconazol/farmacología , Fragmentos de Péptidos/farmacología , Antifúngicos/síntesis química , Arthrodermataceae/fisiología , Técnicas de Química Sintética , Griseofulvina/síntesis química , Humanos , Itraconazol/síntesis química , Fragmentos de Péptidos/síntesis químicaRESUMEN
Besides lung drastic involvement, SARS-CoV-2 severely affected other systems including liver. Emerging epidemiological studies brought the attentions towards liver injury and impairment as a potential outcome of COVID19. Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease (TMPRSS2) are the main cell entry receptors of SARS-CoV-2. We have tested the ability of medications to regulate expression of SARS-CoV-2 receptors. Understanding that may reflect how such medications may affect the level of infectivity and permissibility of the liver following COVID-19. Using transcriptomic datasets, Toxicogenomic Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) and GSE30351, we have tested the ability of ninety common medications to regulate COVID-19 receptors expression in human primary hepatocytes. Most medications displayed a dose-dependent change in expression of receptors which could hint at a potentially more pronounced change with chronic use. The expression level of TMPRSS2 was increased noticeably with a number of medications such as metformin. Within the analgesics, acetaminophen revealed a dose-dependent reduction in expression of ACE2, while non-steroidal anti-inflammatory drugs had mixed effect on receptors expression. To confirm the observed effects on primary human hepatocytes, rat hepatocyte treatments data was obtained from DrugMatrix toxicogenomic database (GSE57805), which showed a similar ACE2 and TMPRSS2 expression pattern. Treatment of common co-morbidities often require chronic use of multiple medications, which may result in an additive increase in the expression of ACE2 and TMPRSS2. More research is needed to determine the effect of different medications on COVID-19 receptors.
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Betacoronavirus/patogenicidad , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Peptidil-Dipeptidasa A/genética , Serina Endopeptidasas/genética , Internalización del Virus/efectos de los fármacos , Acetaminofén/administración & dosificación , Acetaminofén/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Células Cultivadas , Infecciones por Coronavirus/terapia , Relación Dosis-Respuesta a Droga , Griseofulvina/farmacología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Hígado/citología , Hígado/virología , Pandemias , Neumonía Viral/terapia , Ratas , SARS-CoV-2RESUMEN
BACKGROUND: Dermatophytes belonging to the Trichophyton genus are important human pathogens, but they have developed resistance to griseofulvin, the most common antifungal drug used to treat dermatophytosis. OBJECTIVE: This study was aimed to evaluate the antidermatophytic activity of synthetic peptides, as well as mechanisms of action and synergistic effect with griseofulvin. METHODS: Scanning electron microscopy (SEM), atomic force microscopy (AFM) and fluorescence microscopy (FM) were employed to understand the activity and the mechanism of action of peptides. RESULTS: Here we report that synthetic peptides at 50 µg/mL, a concentration 20-fold lower than griseofulvin, reduced the microconidia viability of T. mentagrophytes and T. rubrum by 100%, whereas griseofulvin decreased their viability by only 50% and 0%, respectively. The action mechanism of peptides involved cell wall damage, membrane pore formation and loss of cytoplasmic content. Peptides also induced overproduction of reactive oxygen species (ROS) and enhanced the activity of griseofulvin 10-fold against both fungi, suggesting synergistic effects, and eliminated the toxicity of this drug to human erythrocytes. Docking analysis revealed ionic and hydrophobic interactions between peptides and griseofulvin, which may explain the decline of griseofulvin toxicity when mixed with peptides. CONCLUSION: Therefore, our results strongly suggest six peptides with high potential to be employed alone as new drugs or as adjuvants to enhance the activity and decrease the toxicity of griseofulvin.
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Antifúngicos/farmacología , Griseofulvina/farmacología , Péptidos/síntesis química , Péptidos/farmacología , Esporas Fúngicas/efectos de los fármacos , Trichophyton/efectos de los fármacos , Descubrimiento de Drogas , Farmacorresistencia Fúngica , Sinergismo Farmacológico , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an antifungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.