Article
Contribution of hypermutation to fosfomycin heteroresistance in Escherichia coli
Author/s | Portillo Calderón, Inés María
Ortiz Padilla, Miriam Rodríguez Martínez, José Manuel De Gregorio Iaria, Belén Blázquez, Jesús Rodríguez-Baño, Jesús Pascual Hernández, Álvaro Docobo Pérez, Fernando |
Department | Universidad de Sevilla. Departamento de Microbiología Universidad de Sevilla. Departamento de Medicina |
Publication Date | 2020 |
Deposit Date | 2024-05-27 |
Published in |
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Awards | Premio Mensual Publicación Científica Destacada de la US. Facultad de Medicina |
Abstract | Objectives: To explore the effect of combining defects in DNA repair systems with the presence of fosfomycin-resistant mechanisms to explain the mechanisms underlying fosfomycin heteroresistance phenotypes in Enterobacte ... Objectives: To explore the effect of combining defects in DNA repair systems with the presence of fosfomycin-resistant mechanisms to explain the mechanisms underlying fosfomycin heteroresistance phenotypes in Enterobacteriaceae. Materials and methods: We used 11 clinical Escherichia coli isolates together with isogenic single-gene deletion mutants in the E. coli DNA repair system or associated with fosfomycin resistance, combined with double-gene deletion mutants. Fosfomycin MICs were determined by gradient strip assay (GSA) and broth microdilution (BMD). Mutant frequencies for rifampicin (100 mg/L) and fosfomycin (50 and 200 mg/L) were determined. Using two starting inocula, in vitro fosfomycin activity was assessed over 24 h in growth (0.5-512 mg/L) and time-kill assays (64 and 307 mg/L). Results: Strong and weak mutator clinical isolates and single-gene deletion mutants, except for ΔuhpT and ΔdnaQ, were susceptible by GSA. By BMD, the percentage of resistant clinical isolates reached 36%. Single-gene deletion mutants showed BMD MICs similar to those for subpopulations by GSA. Strong mutators showed a higher probability of selecting fosfomycin mutants at higher concentrations. By combining the two mechanisms of mutation, MICs and ranges of resistant subpopulations increased, enabling strains to survive at higher fosfomycin concentrations in growth monitoring assays. In time-kill assays, high inocula increased survival by 37.5% at 64 mg/L fosfomycin, compared with low starting inocula. Conclusions: The origin and variability of the fosfomycin heteroresistance phenotype can be partially explained by high mutation frequencies together with mechanisms of fosfomycin resistance. Subpopulations should be considered until clinical meaning is established. |
Funding agencies | Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases - European Development Regional Fund 'A way to achi Plan Nacional de I+D+i 2013-2016 |
Project ID. | PI10/02021
REIPI RD12/0015/0010 REIPI RD16/0016/0001 |
Citation | Portillo Calderón, I.M., Ortiz Padilla, M., Rodríguez Martínez, J.M., De Gregorio Iaria, B., Blázquez, J., Rodríguez-Baño, J.,...,Docobo Pérez, F. (2020). Contribution of hypermutation to fosfomycin heteroresistance in Escherichia coli. Journal of Antimicrobial Chemotherapy, Volumen: 75 Número: 8 Páginas: 2066 - 2075 (8), 2066-2075. https://doi.org/10.1093/jac/dkaa131. |
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