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Fosfomycin resistance in  Escherichia coli  results from chromosomal mutations or acquisition of plasmid-mediated genes. Because these mechanisms may be absent in some resistant isolates, we aimed at decipher the genetic basis of fosfomycin resistance in  E. coli . Different groups of isolates were studied: fosfomycin-resistant mutants selected  in vitro  from  E. coli  CFT073 (MIC = 1 mg/L) and two groups (wildtype and non-wildtype) of  E. coli  clinical isolates. Single-nucleotide allelic replacement was performed to confirm the implication of novel mutations into resistance. Induction of  uhpT  expression by glucose-6-phosphate (G6P) was assessed by RT-qPCR. The genome of all clinical isolates was sequenced by MiSeq (Illumina). Two first-step mutants were obtained  in vitro  from CFT073 (MICs, 128 mg/L) with single mutations: G469R in  uhpB  (M3); F384L in  uhpC  (M4). Second-step mutants (MICs, 256 mg/L) presented additional mutations: R282V in  galU  (M7 from M3); Q558 ∗  in  lon  (M8 from M4). Introduction of  uhpB  or  uhpC  mutations by site-directed mutagenesis conferred a 128-fold increase in fosfomycin MICs, whereas single mutations in  galU  or  lon  were only responsible for a 2-fold increase. Also, these mutations abolished the induction of  uhpT  expression by G6P. All 14 fosfomycin-susceptible clinical isolates (MICs, 0.5–8 mg/L) were devoid of any mutation. At least one genetic change was detected in all but one fosfomycin-resistant clinical isolates (MICs, 32 – >256 mg/L) including 8, 17, 18, 5, and 8 in  uhpA ,  uhpB ,  uhpC ,  uhpT , and  glpT  genes, respectively. In conclusion, novel mutations in  uhpB  and  uhpC  are associated with fosfomycin resistance in  E. coli  clinical isolates.

Novel Chromosomal Mutations Responsible for Fosfomycin Resistance in Escherichia coli