Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

[Assessing the profile and nutritional intake of an Ibero-American group of nutrition postgraduate students]. / Valoración del perfil e ingesta de nutrientes de un grupo de estudiantes iberoamericanos de postgrados en nutrición.

INTRODUCTION: Dietary habits have a great influence on people health of, and its study is extremely important to proof adaptation to current recommendations in order to develop nutritional education and/or supplementation policies adjusted to reality. MATERIAL AND METHODS: A descriptive cross study with the participation of postgraduate students. Participants were selected using non-probability accidental sampling accidental. Information was sent by e-mail, including a questionnaire on socio-demographic characteristics and a 3-day dietary record. We obtained a sample of n = 50 participants. The 3-day dietary records were evaluated with NutrIber software and the data obtained were treated using the statistical software SPSS 15. RESULTS AND DISCUSSION: The profile of the students was 80% females and 20% males, mean age 33.7 ± 9.32 years, and body mass index of 22.91 ± 4.07. All groups have an excessive consumption of proteins and lipids and carbohydrates deficit. At the macro-story is remarkable that no group covers iodine recommended nutrient intake, and that no group of women covers the recommendations for fiber, folic acid and iron intake. CONCLUSIONS: Further studies are needed to confirm the results found. However, it can be concluded that urban populations in Latin America are increasingly closer to the model of Western diet, rich in protein and fat and low in carbohydrates, fiber and micronutrients, which is indicative of poor diets in whole grains, fruits and vegetables.

Introducción: Los hábitos alimentarios tienen una gran influencia sobre la salud de las personas, por ello es de suma importancia profundizar en su estudio para comprobar su adaptación a las recomendaciones actuales y poder realizar políticas de educación nutricional y/o suplementación ajustadas a la realidad. Material y métodos: Estudio transversal descriptivo con la colaboración de estudiantes de postgrado. Los participantes se seleccionaron mediante muestreo no probabilístico accidental enviando vía mail la información del estudio, realizado mediante un cuestionario sobre sus características socio-demográficas y un registro dietético de 3 días. La muestra estuvo formada por n = 50 participantes. Los registros dietéticos de 3 días se valoraron con el software NutrIber y los datos obtenidos fueron tratados mediante el software estadístico SPSS 15. Resultados y discusión: El perfil de los estudiantes es de 80% mujeres y 20% hombres, con edad media de 33,7 ± 9,32 AÑOs, e índice de masa corporal de 22,91 ± 4,07. Todos los grupos presentan un consumo excesivo de proteínas y lípidos y deficitario en glúcidos. En cuanto a los micronutrientes es destacable que ningún grupo cubre las ingestas recomendadas de yodo, y que ningún grupo de mujeres cubre las recomendaciones de ingesta de fibra, ácido fólico ni hierro. Conclusiones: Son necesarios más estudios para confirmar los resultados hallado, sin embargo, se puede concluir que las poblaciones urbanas de Latinoamérica cada vez se acercan más al modelo de dieta occidental, rica en proteínas y grasas y pobre en glúcidos, fibra y micronutrientes, lo que es indicativo de dietas pobres en cereales integrales, frutas y verduras.

Valoración del perfil e ingesta de nutrientes de un grupo de estudiantes iberoamericanos de postgrados en nutrición / Assesing the profile and nutritional intakes of an ibero-american group of nutrition postgraduate students

Introducción: Los hábitos alimentarios tienen una gran influencia sobre la salud de las personas, por ello es de suma importancia profundizar en su estudio para comprobar su adaptación a las recomendaciones actuales y poder realizar políticas de educación nutricional y/o suplementación ajustadas a la realidad. Material y métodos: Estudio transversal descriptivo con la colaboración de estudiantes de postgrado. Los participantes se seleccionaron mediante muestreo no probabilístico accidental enviando vía mail la información del estudio, realizado mediante un cuestionario sobre sus características socio-demográficas y un registro dietético de 3 días. La muestra estuvo formada por n = 50 participantes. Los registros dietéticos de 3 días se valoraron con el software NutrIber y los datos obtenidos fueron tratados mediante el software estadístico SPSS 15. Resultados y discusión: El perfil de los estudiantes es de 80% mujeres y 20% hombres, con edad media de 33,7 ± 9,32 años, e índice de masa corporal de 22,91 ± 4,07. Todos los grupos presentan un consumo excesivo de proteínas y lípidos y deficitario en glúcidos. En cuanto a los micronutrientes es destacable que ningún grupo cubre las ingestas recomendadas de yodo, y que ningún grupo de mujeres cubre las recomendaciones de ingesta de fibra, ácido fólico ni hierro. Conclusiones: Son necesarios más estudios para confirmar los resultados hallado, sin embargo, se puede concluir que las poblaciones urbanas de Latinoamérica cada vez se acercan más al modelo de dieta occidental, rica en proteínas y grasas y pobre en glúcidos, fibra y micronutrientes, lo que es indicativo de dietas pobres en cereales integrales, frutas y verduras (AU)

Introduction: Dietary habits have a great influence on people health of, and its study is extremely important to proof adaptation to current recommendations in order to develop nutritional education and/or supplementation policies adjusted to reality. Material and methods: A descriptive cross study with the participation of postgraduate students. Participants were selected using non-probability accidental sampling accidental. Information was sent by e-mail, including a questionnaire on socio-demographic characteristics and a 3-day dietary record. We obtained a sample of n = 50 participants. The 3-day dietary records were evaluated with NutrIber software and the data obtained were treated using the statistical software SPSS 15. Results and discussion: The profile of the students was 80% females and 20% males, mean age 33.7 ± 9.32 years, and body mass index of 22.91 ± 4.07. All groups have an excessive consumption of proteins and lipids and carbohydrates deficit. At the macrostory is remarkable that no group covers iodine recommended nutrient intake, and that no group of women covers the recommendations for fiber, folic acid and iron intake. Conclusions: Further studies are needed to confirm the results found. However, it can be concluded that urban populations in Latin America are increasingly closer to the model of Western diet, rich in protein and fat and low in carbohydrates, fiber and micronutrients, which is indicative of poor diets in whole grains, fruits and vegetables (AU)