Publication: Mecanismos de resistencia a antibióticos: biología estructural de proteínas del reciclaje de la pared bacteriana de "P. aeruginosa"
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2017-11-27
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Universidad Complutense de Madrid
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Abstract
En el año 2014 la organización mundial de la salud publicó un informe confirmando que la resistencia de las bacterias a los antibióticos ha alcanzado niveles alarmantes en muchas partes del mundo. Las infecciones causadas por bacterias resistentes son cada vez más frecuentes e invasivas debido al mal uso de los antibióticos y a que las bacterias han desarrollado diversos mecanismos de resistencia para sobrevivir a la acción de los antibióticos. La pared bacteriana presenta la doble característica de ser una estructura vital y exclusiva de estos microorganismos (no existen homólogos en células eucariotas). Es por ello que el diseño o hallazgo de moléculas dirigidas contra la pared constituye una herramienta poderosa y segura para combatir las infecciones bacterianas. En esta tesis se estudian cuatro enzimas claves en el proceso de reciclaje de la pared celular del patógeno oportunista Pseudomonas aeruginosa. Se ha resuelto la estructura tridimensional de tres transglicosilasas líticas (LTs): SltB3, Slt y MltF. Estas enzimas son las responsables de romper el enlace glicosídico en el proceso de reciclaje de la pared. Este proceso involucra gran cantidad de enzimas tanto en el periplasma como en el citoplasma y está ligado tanto al mantenimiento de la bacteria como a la resistencia a antibióticos. En este trabajo se analiza también el dominio de unión del efector (EBD) del regulador transcripcional AmpR, que es el encargado de regular la expresión de b-lactamasas y que conecta el reciclaje del peptidoglicano con la resistencia a antibióticos...
Among all of the bacterial resistance complication, gram-negative pathogens are particularly worrying as they are becoming resistant to nearly all drugs. Treating infections of pan-resistant or nearly pan-resistant Gram negative microorganisms is becoming an increasingly common challenge in many hospitals. The nefarious opportunistic pathogen Pseudomonas aeruginosa causes nosocomial infections such us pneumonia, bloodstream infections, urinary track infections, and surgical site infections. About 13% of severe healthcare-associated infections are caused by multidrug resistant strains of P. aeruginosa, meaning that almost all classes of antibiotics no longer cure these infections. The bacterial cell wall is an elastic polymer that defines the shape of the bacterium and prevents cell lysis under high osmotic pressure. Since the cell wall is a unique part of the bacteria it becomes very interesting target. Cell-wall remodelling and cell-wall biosynthesis have to be coordinated in careful manner. Lytic transglycosylases (LTs) cleave the non-hydrolytic fragmentation of the b- 1,4-glycosidic bond between the main components of peptidoglycan (PG): NAM and NAG. The mechanism by which LTs catalyse the fragmentation is unique...
Among all of the bacterial resistance complication, gram-negative pathogens are particularly worrying as they are becoming resistant to nearly all drugs. Treating infections of pan-resistant or nearly pan-resistant Gram negative microorganisms is becoming an increasingly common challenge in many hospitals. The nefarious opportunistic pathogen Pseudomonas aeruginosa causes nosocomial infections such us pneumonia, bloodstream infections, urinary track infections, and surgical site infections. About 13% of severe healthcare-associated infections are caused by multidrug resistant strains of P. aeruginosa, meaning that almost all classes of antibiotics no longer cure these infections. The bacterial cell wall is an elastic polymer that defines the shape of the bacterium and prevents cell lysis under high osmotic pressure. Since the cell wall is a unique part of the bacteria it becomes very interesting target. Cell-wall remodelling and cell-wall biosynthesis have to be coordinated in careful manner. Lytic transglycosylases (LTs) cleave the non-hydrolytic fragmentation of the b- 1,4-glycosidic bond between the main components of peptidoglycan (PG): NAM and NAG. The mechanism by which LTs catalyse the fragmentation is unique...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I, leída el 02-12-2016