RESUMEN
Gentamicin (GEN), a widely used broad-spectrum antibiotic, faces challenges amid the global emergency of antimicrobial resistance. This study aimed to explore the synergistic effects of zinc oxide nanoparticles (ZnO NPs) in combination with GEN on the bactericidal activity against various bacterial strains. Results showed ZnO NPs with MICs ranging from 0.002 to 1.5 µg/mL, while the precursor salt displayed a MIC range of 48.75-1560 µg/mL. Chitosan (CS)-capped ZnO NPs exhibited even lower MICs than their uncapped counterparts, with the CS-capped synthesized ZnO NPs demonstrating the lowest values. Minimal bactericidal concentrations (MBC) aligned with MIC trends. Combinations of CS-capped synthesized ZnO NPs and GEN proved highly effective, inhibiting bacterial growth at significantly lower concentrations than GEN or ZnO NPs alone. This phenomenon may be attributed to the conformation of CS on the ZnO NPs' surface, enhancing the positive particle surface charge. This possibly facilitates a more effective interaction between ZnO NPs and microorganisms, leading to increased accumulation of zinc and GEN within bacterial cells and an overproduction of reactive oxygen species (ROS). It's crucial to note that, while this study did not specifically involve resistant strains, its primary focus remains on enhancing the overall antimicrobial activity of gentamicin. The research aims to contribute to addressing the global challenge of antimicrobial resistance, recognizing the urgent need for effective strategies to combat this critical issue. The findings, particularly the observed synergy between ZnO NPs and GEN, hold significant implications for repositioning the first-line antibiotic GEN.
RESUMEN
Nanotechnology is a very promising technological tool to combat health problems associated with the loss of effectiveness of currently used antibiotics. Previously, we developed a formulation consisting of a chitosan and tween 80-decorated alginate nanocarrier that encapsulates rifampicin and the antioxidant ascorbic acid (RIF/ASC), intended for the treatment of respiratory intracellular infections. Here, we investigated the effects of RIF/ASC-loaded NPs on the respiratory mucus and the pulmonary surfactant. In addition, we evaluated their cytotoxicity for lung cells in vitro, and their biodistribution on rat lungs in vivo after their intratracheal administration. Findings herein demonstrated that RIF/ASC-loaded NPs display a favorable lung biocompatibility profile and a uniform distribution throughout lung lobules. RIF/ASC-loaded NPs were mainly uptaken by lung macrophages, their primary target. In summary, findings show that our novel designed RIF/ASC NPs could be a suitable system for antibiotic lung administration with promising perspectives for the treatment of pulmonary intracellular infections.
Asunto(s)
Alginatos/química , Ácido Ascórbico/química , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Nanopartículas/química , Rifampin/metabolismo , Rifampin/toxicidad , Células A549 , Alginatos/metabolismo , Alginatos/toxicidad , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/toxicidad , Ácido Ascórbico/metabolismo , Ácido Ascórbico/toxicidad , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Línea Celular , Línea Celular Tumoral , Quitosano/metabolismo , Quitosano/toxicidad , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidad , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Masculino , Nanopartículas/metabolismo , Nanopartículas/toxicidad , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/toxicidad , Polímeros/metabolismo , Polímeros/toxicidad , Ratas , Ratas Wistar , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Rifampin/farmacología , Porcinos , Distribución TisularRESUMEN
The aim of this study was to design a nanocarrier system for inhalation delivery of rifampicin (RIF) in combination with ascorbic acid (ASC), namely constituted of sodium alginate coated with chitosan and Tween 80 (RIF/ASC NPs) as a platform for the treatment of pulmonary tuberculosis infection. A Box-Behnken experimental design and response surface methodology (RSM) were applied to elucidate and evaluate the effects of several factors on the nanoparticle properties. On the other hand, it was found that RIF/ASC NPs were less cytotoxic than the free RIF, showing a significantly improved activity against nine clinical strains of Mycobacterium tuberculosis (M. tb) in comparison with the free drug. RIF/ASC NPs had an average particle size of 324.0 ± 40.7 nm, a polydispersity index of 0.226 ± 0.030, and a zeta potential of - 28.52 ± 0.47 mV and the surface was hydrophilic. The addition of sucrose (1% w/v) to the nanosuspension resulted in the formation of a solid pellet easily redispersible after lyophilization. RIF/ASC NPs were found to be stable at different physiological pH values. In summary, findings of this work highlight the potential of the RIF/ASC NP-based formulation development herein to deliver RIF in combination with ASC through pulmonary route by exploring a non-invasive route of administration of this antibiotic, increasing the local drug concentrations in lung tissues, the primary infection site, as well as reducing the risk of systemic toxicity and hence improving the patient compliance.