Vesículas de membrana externa como mecanismo defensivo contra antimicrobianos en salmonella enterica serovares typhi y typhimurium
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Fecha
2019
Profesor/a Guía
Facultad/escuela
Idioma
es
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Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Salmonella enterica serovar Typhi es el agente etiológico de la fiebre tifoidea, una
enfermedad infecciosa seria con un porcentaje de letalidad de alrededor del 30%
en la era preantibióticos. El uso de antimicrobianos reduce ampliamente la
mortalidad de esta enfermedad, sin embargo, la constante emergencia de cepas
resistentes hace significativamente más complicado su tratamiento. Por esto, se
vuelve importante estudiar mecanismos de resistencia alternativos para
desarrollar tratamientos nuevos.
Este estudio se enfoca en las vesículas de membrana externa (OMVs),
compartimentos lipoproteicos nanométricos que son parte de complejos sistemas
de respuesta al estrés. A la luz de estos antecedentes, nos preguntamos sobre
el rol que desempeñan las OMVs en la resistencia antibiótica, por lo que
decidimos evaluar tanto el efecto de la presencia de OMVs en la actividad de los
antibióticos, como los determinantes de estos efectos, mediante ensayos de
determinación de concentración mínima inhibitoria complementados con OMVs
extraídas de un conjunto de mutantes de Salmonella enterica hipervesiculadoras,
y S. Typhi tratada con dosis subletales de antimicrobianos no relacionados.
Nuestros resultados más importantes muestran que las OMVs median un
importante incremento en la resistencia a polimixina B, un oligopéptido catiónico
que se intercala entre los fosfolípidos, formando poros hasta matar a la bacteria.
Este efecto parece depender tanto de la concentración de las OMVs como de su
naturaleza (por ejemplo, sus componentes). Además, dosis subletales de
ampicilina parecen provocar una respuesta al estrés que promueve la formación
de OMVs, y subsecuentemente, incrementan la resistencia a polimixina B.
En resumen, las OMVs parecen constituir un mecanismo defensivo inespecífico
con efecto sobre este antimicrobiano, y sus implicancias en la futura acumulación
de mutaciones requiere más estudio, lo que apoya la importancia de este trabajo.
Salmonella enterica serovar Typhi is the etiological agent of typhoid fever, a severe infective disease which resulted in a death toll of around 30% in the preantibiotic era. The use of antibiotics greatly reduces the mortality of typhoid fever, but the continuous emergence of resistant strains complicates significantly the treatment. Thus, it becomes important to study alternative resistance mechanisms to develop new treatments. This study sets its focus on outer membrane vesicles (OMVs), nanosized lipoprotein compartments which some reports have them set as part of complex stress response systems. Under this insight, we wondered about the role OMVs possess in antibiotic resistance; thus, we decided to evaluate both the effect of the presence of OMVs on antibiotic activity and the determinants of such effects, by minimum inhibitory concentration assays complemented with OMVs extracted from either a set of hypervesiculating Salmonella enterica mutants and WT S. Typhi treated with sublethal doses of antibiotics. Our most prominent results show OMVs mediate an important increase in the resistance to polymyxin B, a cationic lipopeptide that locks itself between phospholipids, forming pores until life is no longer sustainable. This effect seems to rely both in the concentration of OMVs and the nature of OMVs (i.e. their components). Additionally, sublethal doses of ampicillin seem to trigger a stress response which promotes OMV production, and subsequently, increased resistance towards polymyxin B. Overall, OMVs seem to be a non-specific defensive mechanism with effect against this antibiotic, and its implications on future cumulative mutations require further study, hence remarking the importance of this work.
Salmonella enterica serovar Typhi is the etiological agent of typhoid fever, a severe infective disease which resulted in a death toll of around 30% in the preantibiotic era. The use of antibiotics greatly reduces the mortality of typhoid fever, but the continuous emergence of resistant strains complicates significantly the treatment. Thus, it becomes important to study alternative resistance mechanisms to develop new treatments. This study sets its focus on outer membrane vesicles (OMVs), nanosized lipoprotein compartments which some reports have them set as part of complex stress response systems. Under this insight, we wondered about the role OMVs possess in antibiotic resistance; thus, we decided to evaluate both the effect of the presence of OMVs on antibiotic activity and the determinants of such effects, by minimum inhibitory concentration assays complemented with OMVs extracted from either a set of hypervesiculating Salmonella enterica mutants and WT S. Typhi treated with sublethal doses of antibiotics. Our most prominent results show OMVs mediate an important increase in the resistance to polymyxin B, a cationic lipopeptide that locks itself between phospholipids, forming pores until life is no longer sustainable. This effect seems to rely both in the concentration of OMVs and the nature of OMVs (i.e. their components). Additionally, sublethal doses of ampicillin seem to trigger a stress response which promotes OMV production, and subsequently, increased resistance towards polymyxin B. Overall, OMVs seem to be a non-specific defensive mechanism with effect against this antibiotic, and its implications on future cumulative mutations require further study, hence remarking the importance of this work.
Notas
Tesis (Licenciado en Biología)
Palabras clave
Salmonella Entérica, Vesículas de Membrana Externa, Agentes Anti-Infecciosos