RESUMEN
Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections.
Asunto(s)
Antibacterianos , Colistina , Diterpenos , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Colistina/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Animales , Antibacterianos/farmacología , Ratones , Diterpenos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Bacterias Gramnegativas/efectos de los fármacos , Sinergismo Farmacológico , Femenino , HumanosRESUMEN
OBJECTIVE: The aim of the present study is to explore the impact of the tet(A) type I variant (tetA-v1) on its fitness effect in Klebsiella pneumoniae. METHODS: Clinical K. pneumoniae strains were utilized as parental strains to generate strains carrying only the plasmid vector (pBBR1MCS-5) or the tetA-v1 recombinant plasmid (ptetA-v1). Antimicrobial susceptibility testing was conducted to estimate the contribution of tetA-v1 to drug resistance. Plasmid stability was evaluated by serial passage over 10 consecutive days in the absence of tigecycline. Biological fitness was examined through growth curve analysis, in vitro competition assays and a neutropenic mouse thigh infection model. RESULTS: A 2-4-fold increase in tigecycline MIC was observed following the acquisition of tetA-v1. Without tigecycline treatment, the stability of ptetA-v1 plasmids has been decreasing since day 1. The ptetA-v1 plasmid in Kp89, Kp91, and Kp93 exhibited a decrease of about 20% compared to the pBBR1MCS-5 plasmid. The acquisition of the tetA-v1 gene could inhibit the growth ability of K. pneumoniae strains both in vitro and in vivo. tetA-v1 gene imposed a fitness cost in K. pneumoniae, particularly in the CRKP strain Kp51, with a W value of approximately 0.56. CONCLUSION: The presence of tetA-v1 is associated with a significant fitness cost in K. pneumoniae in the absence of tigecycline, both in vitro and in vivo.
Asunto(s)
Antibacterianos , Infecciones por Klebsiella , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Plásmidos , Tigeciclina , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/genética , Tigeciclina/farmacología , Animales , Antibacterianos/farmacología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/tratamiento farmacológico , Plásmidos/genética , Ratones , Proteínas Bacterianas/genética , Minociclina/análogos & derivados , Minociclina/farmacología , Humanos , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana/genética , Aptitud Genética , AntiportadoresRESUMEN
The present paper introduces an innovative strain energy function (SEF) for incompressible anisotropic fiber-reinforced materials. This SEF is specifically designed to understand the mechanical behavior of carbon fiber-woven fabric. The considered model combines polyconvex invariants forming an integrity basisin polynomial form, which is inspired by the application of Noether's theorem. A single solution can be obtained during the identification because of the relationship between the SEF we have constructed and the material parameters, which are linearly dependent. The six material parameters were precisely determined through a comparison between the closed-form solutions from our model and the corresponding tensile experimental data with different stretching ratios, with determination coefficients consistently reaching a remarkable value of 0.99. When considering only uniaxial tensile tests, our model can be simplified from a quadratic polynomial to a linear polynomial, thereby reducing the number of material parameters required from six to four, while the fidelity of the model's predictive accuracy remains unaltered. The comparison between the results of numerical calculations and experiments proves the efficiency and accuracy of the method.