Artículo
Interplay Among Different Fosfomycin Resistance Mechanisms in Klebsiella Pneumoniae
Autor/es | Ortiz Padilla, M.
Portillo Calderón, I. De Gregorio Iaria, Belén Blázquez, J. Rodríguez-Baño, Jesús Pascual Hernández, Álvaro Rodríguez Martínez, José Manuel Docobo Pérez, Fernando |
Departamento | Universidad de Sevilla. Departamento de Microbiología Universidad de Sevilla. Departamento de Medicina |
Fecha de publicación | 2021 |
Fecha de depósito | 2023-01-10 |
Publicado en |
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Resumen | The objectives of this study were to characterize the role of the uhpT, glpT, and fosA genes in fosfomycin resistance in Klebsiella pneumoniae and evaluate the use of sodium phosphonoformate (PPF) in combination with ... The objectives of this study were to characterize the role of the uhpT, glpT, and fosA genes in fosfomycin resistance in Klebsiella pneumoniae and evaluate the use of sodium phosphonoformate (PPF) in combination with fosfomycin. Seven clinical isolates of K. pneumoniae and the reference strain (ATCC 700721) were used, and their genomes were sequenced. DuhpT, DglpT, and DfosA mutants were constructed from two isolates and K. pneumoniae ATCC 700721. Fosfomycin susceptibility testing was done by the gradient strip method. Synergy between fosfomycin and PPF was studied by checkerboard assay and analyzed using SynergyFinder. Spontaneous fosfomycin mutant frequencies at 64 and 512mg/liter, in vitro activity using growth curves with fosfomycin gradient concentrations (0 to 256mg/liter), and time-kill assays at 64 and 307mg/liter were evaluated with and without PPF (0.623mM). The MICs of fosfomycin against the clinical isolates ranged from 16 to ≥1,024mg/liter. The addition of 0.623mM PPF reduced fosfomycin MIC between 2- and 8-fold. Deletion of fosA led to a 32-fold decrease. Synergistic activities were observed with the combination of fosfomycin and PPF (most synergistic area at 0.623mM). The lowest fosfomycin-resistant mutant frequencies were found in ΔfosA mutants, with decreases in frequency from 1.69×10-1 to 1.60×10-5 for 64mg/liter of fosfomycin. In the final growth monitoring and time-kill assays, fosfomycin showed a bactericidal effect only with the deletion of fosA and not with the addition of PPF. We conclude that fosA gene inactivation leads to a decrease in fosfomycin resistance in K. pneumoniae. The pharmacological approach using PPF did not achieve enough activity, and the effect decreased with the presence of fosfomycin-resistant mutations. |
Agencias financiadoras | Ministerio de Economía y Competitividad (MINECO). España Junta de Andalucía Innovative Medicines Initiative (IMI) |
Identificador del proyecto | PI16/01824
REIPI RD12/0015/0010 REIPI RD16/0016/0001 PI-0044 115523 115620 115737 |
Cita | Ortiz Padilla, M., Portillo Calderón, I., de Gregorio Iaria, B., Blázquez, J., Rodríguez Baño, J., Pascual Hernández, Á.,...,Docobo Pérez, F. (2021). Interplay Among Different Fosfomycin Resistance Mechanisms in Klebsiella Pneumoniae. Antimicrobial Agents and Chemotherapy, 65 (3), e01911-20. https://doi.org/10.1128/AAC.01911-20. |
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