Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5397_Библиотеки_им_академика_М_И_Перельмана

The development of resistance to pathogens is a major and increasing challenge in the ght against IDs. Pathogens may acquire resistance by a number of mecha­nisms, including the production of drug-inactivating enzymes, an intracellular life cycle, biolm formation, decreased metabolic activity, or the fact that they are obli­gate intracellular pathogens (Munita and Arias 2016). Ineffectiveness against intra­cellular infections may be caused by poor drug diffusion through the membrane of the host cells and its active efux via drug transporters (Carryn etal. 2003). Since pathogens and drug molecules are not colocalized inside host cells, effectiveness is reduced, adding another layer of complication. Aminoglycosides, for instance, pre­fer to accumulate in the lysosomes, making them useless against cytosolic patho­gens (Tulkens and Trouet 1978). Therefore, methods that boost drug accumulation within cells and direct medications to specic subcellular sites may be more effec­tive. By enclosing anti-infectives in NCs, it may be possible to improve their absorp­tion by cells and to modify their intracellular disposition. Improvements in gentamicin administration to cytoplasmic organisms like Listeria monocytogenes and Salmonella typhimurium were tried by Lutwyche etal. (1998). Fusogenic lipo­somes, which are stable at neutral pH but dissolve in the acidic environment of endolysosomes, were used to encapsulate gentamycin. The medication is released into the cytoplasm as the endosomal membrane is destabilized by lipid fusion. The scientists used two liposomal formulations, one having a uorescence resonance energy transfer pair and the other without, to verify the acid-mediated disintegration of the liposomes. This mixture’s low baseline uorescence was due to the closeness of the uorescent molecules. However, when the solution was made acidic, the lipo­somes ruptured and the lipids mingled, which dequenched the uorescence. Gentamicin loaded into pH-sensitive liposomes was three times as effective as the free antibiotic in an invitro model of infection with recombinant S. typhimurium. Although pH-insensitive liposomes were taken up by cells to a greater extent, their activity lagged behind that of the pH-sensitive formulation. The authors uores­cently labeled liposomes that were released and metabolized by cellular enzymes to investigate the process. Only pH-sensitive liposomes produced the marker intracel­lularly in mouse macrophages, as shown by confocal imaging. Balomycin, an endosome acidication inhibitor, suppressed marker release. The importance of intracellular targeting was shown, and the molecular specics of the roles played by each component of the formulation were presented in this work.