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Gliotoxin is a fungal secondary metabolite with impact on health and agriculture since it might act as virulence factor and contaminate human and animal food. Homologous gliotoxin (GT) gene clusters are spread across a number of fungal species although if they produce GT or other related epipolythiodioxopiperazines (ETPs) remains obscure. Using bioinformatic tools, we have identified homologous gli gene clusters similar to the A. fumigatus GT gene cluster in several fungal species. In silico study led to in vitro confirmation of GT and Bisdethiobis(methylthio)gliotoxin (bmGT) production in fungal strain cultures by HPLC detection. Despite we selected most similar homologous gli gene cluster in 20 different species, GT and bmGT were only detected in section Fumigati species and in a Trichoderma virens Q strain. Our results suggest that in silico gli homology analyses in different fungal strains to predict GT production might be only informative when accompanied by analysis about mycotoxin production in cell cultures.

Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital-acquired and community infections and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin (GT) is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that GT shows antimicrobial activity against S. aureus in vitro, albeit its efficacy against multidrug-resistant strains such as MRSA or vancomycin-intermediate S. aureus (VISA) strainsis not known. This work aimed to evaluate the antibiotic efficacy of GT as monotherapy or in combination with other therapeutics against MRSA in vitro and in vivo using a Caenorhabditis elegans infection model.

[Introducción/Objetivos]: la gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Es un metabolito secundario perteneciente a la familia de las epipolitiodioxopiperazinas, caracterizada por la presencia de un puente disulfuro interno en un anillo de piperazina, que parece ser necesario para la mayoría de las propiedades biológicas de este compuesto. Se ha demostrado que la gliotoxina es un factor de virulencia durante la aspergilosis invasiva y presenta una toxicidad notable contra las células de mamíferos. Sin embargo, las evidencias científicas sobre su potencial actividad antimicrobiana son escasas. Por lo tanto, este trabajo tiene como objetivo evaluar su eficacia antibiótica contra microorganismos de interés clínico como Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa; y antifúngico contra Candida albicans y Candida glabrata. [Material y métodos]: la sensibilidad a la gliotoxina de diferentes cepas (incluidas las farmacorresistentes) de los microorganismos indicados se analizó por diferentes métodos: métodos de difusión en disco (antibiogramas/antifungigramas), estudio de curvas de tiempo-mortalidad, métodos de microdilución y ensayo MTT. Para los aislados de Candida, los resultados fueron confirmados mediante el análisis de la muerte celular por citometría de flujo. [Resultados]: Los resultados sugieren una potente actividad antimicrobiana de gliotoxina contra Candida albicans y Staphylococcus aureus, incluso en las cepas resistentes a azoles y a meticilina, respectivamente. En el caso de Escherichia coli y Candida glabrata, la gliotoxina ejerce una acción antimicrobiana moderada. Sin embargo, Pseudomonas aeruginosa parece ser resistente a la gliotoxina. [Conclusiones]: Nuestros resultados indican que la gliotoxina es efectiva contra Candida albicans y Staphylococcus aureus por lo que podría usarse como una alternativa para el tratamiento de infecciones causadas por cepas resistentes a antibiót

[Background] Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in immunocompromised oncohematology pediatric patients. This is mainly due to the absence of optimal diagnostic modalities, which hamper early specific disease detection and treatment. Thus, diagnosis of IA is still challenging and constitutes a major problem during management of pediatric patients at risk of infection, where the number of studies validating different diagnosis biomarkers is more limited. In a previous study, we demonstrated the high diagnostic accuracy of bis(methyl)gliotoxin(bmGT) compared to GM for IPA diagnosis in adults. The objective of this study is to show bmGT suitability for IPA diagnosis in oncopediatric patients in comparison with GM, monitoring the course of bmGT concentration in serum during voriconazole treatment., [Materials/methods] The presence and concentration of bmGT and voriconazole in sequential serum series from 9 oncopediatric patients with febrile neutropenia (retrospective and prospective samples) were simultaneously quantified by High Performance Thin Layer Chromatography (HPTLC) and confirmed using LC/MS/MS by an independent lab., [Results] HPTLC allowed simultaneous sensitive detection of bmGT and voriconazole in serum and BAL of pediatric patients confirmed by LC/MS/MS. We present two patients (17 and 36 months). In the phase of prolonged neutropenia, fever, hypoxemia and pulmonary infiltration compatible with Aspergillosis in high resolution CT are started. In one patient, bmGT was detected earlier than GM, allowing early initiation of treatment, with the voriconazole treatment the GM was negativized and the bmGT levels decreased. In the second patient, GM was negative and bmGT positive in serum and BAL, so treatment with voriconazole was started, then a decrease in bmGT values was detected coinciding with the patient clinical improvement., [Conclusions] The determination of bmGT in pediatric patients allowed the early diagnosis and effective treatment of two cases of IA, being a promising tool in neutropenic pediatric patients at risk of IPA. Identification of bmGT by HPTLC has been confirmed by LC/MS/MS indicating the presence of this biomarker during IPA in pediatric population. Analyses to establish the performance of serum bmGT detection together with beta-d-Glucan, PCR and IL8 to diagnose IPA in pediatric oncohematological patients are ongoing.

[Introducción/Objetivos]: las bacterias resistentes a múltiples fármacos como el Staphylococcus aureus resistente a meticilina (MRSA) se encuentran entre las principales causas de infecciones adquiridas en el hospital o en la comunidad, y representan un desafío para el sistema de salud. Por lo tanto, es importante encontrar nuevos medicamentos que muestren actividad contra estas bacterias, tanto en monoterapia como en combinación con otros medicamentos antimicrobianos. La gliotoxina es una micotoxina producida por Aspergillus fumigatus y otros hongos del género Aspergillus. Alguna evidencia sugiere que la gliotoxina muestra actividad antimicrobiana, especialmente contra S. aureus. Este trabajo tiene como objetivo evaluar la eficacia antibiótica de la gliotoxina como monoterapia o en combinación con otros agentes terapéuticos contra MRSA in vitro e in vivo utilizando un modelo de infección por C. elegans., [Material y métodos]: La sensibilidad de MRSA ATCC700699 contra la gliotoxina se analizó mediante diferentes métodos: difusión en disco, curvas de mortalidad-tiempo y ensayos de microdilución. Los efectos sinérgicos de la gliotoxina con otros medicamentos antiestafilocócicos (vancomicina, ácido fusídico y linezolid) se probaron mediante un ensayo de tablero de ajedrez. Los gusanos sincronizados de C. elegans L4 se infectaron con MRSA. El cultivo se complementó por separado con gliotoxina, vancomicina o su combinación a diferentes concentraciones. La tasa de supervivencia de C. elegans se evaluó manualmente cada 12 h durante 4 días., [Resultados]: El análisis de sensibilidad de MRSA contra la gliotoxina mostró que la gliotoxina tiene una potente actividad antimicrobiana (MIC = 2 µg / ml). Además, se observó actividad sinérgica, cuando la gliotoxina se combinó con vancomicina y ácido fusídico, usando ensayos de tablero de ajedrez y curvas de muerte. Este efecto sinérgico fue confirmado por el software CalcuSyn (IC = 0.15 para 1 µg / ml de gliotoxina combinada con 2 µg / ml de vancomicina). El estudio in vivo de la infección por S. aureus en un modelo de C. elegans mostró que el tratamiento combinado de vancomicina con gliotoxina aumentó un 70% en la tasa de supervivencia de los gusanos infectados con MRSA., [Conclusiones]: nuestros resultados sugieren que la gliotoxina es efectiva contra las cepas de MRSA, lo que indica su posible uso como un nuevo fármaco contra las infecciones por MRSA.

Microbiota have emerged as key modulators of both the carcinogenic process and the immune response against cancer cells, and, thus, it seems to influence the efficacy of immunotherapy. While most studies have focused on analyzing the influence of gut microbiota, its composition substantially differs from that in the lung. Here, we describe how microbial life in the lungs is associated with host immune status in the lungs and, thus, how the identification of the microbial populations in the lower respiratory tract rather than in the gut might be key to understanding the lung carcinogenic process and to predict the efficacy of different treatments. Understanding the influence of lung microbiota on host immunity may identify new therapeutic targets and help to design new immunotherapy approaches to treat lung cancer.

BackgroundIbrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis. ObjectiveThe aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida. MethodsIbrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated. ResultsIbrexafungerp MICs ranged from 0.016 to >= 8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016-0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06->= 8 mg/L). Modal MICs/MIC(50)s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis. ConclusionIbrexafungerp showed a potent in vitro activity against Candida.