title: Molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli.
abstract: To clarify the molecular mechanisms of fosfomycin resistance in clinical isolates of Escherichia coli, the murA, glpT, uhpT, uhpA, ptsI and cyaA genes were sequenced from six fosfomycin-resistant isolates. Two strains were found to harbour a mutation in the murA gene that leads to an amino acid substitution (Asp369Asn or Leu370Ile) in the target protein. The remaining four strains carried specific mutations in the glpT gene; one strain possessed a mutation and the other three strains possessed truncated versions of the GlpT transporter owing either to the presence of insertion sequences or a deletion in the coding region of the gene. Two of the strains with truncated GlpT had also lost the entire uhpT gene, which encodes another fosfomycin transporter. Uptake of specific substrates for the transporters was either totally blocked or reduced in strains possessing truncated forms of GlpT or those lacking the uhpT gene. Escherichia coli strains expressing an amino-acid-substituted MurA were at least eight-fold more resistant to fosfomycin than the strain overproducing wild-type MurA. In conclusion, novel amino acid substitutions in MurA or the loss of function of transporters were identified as mechanisms of fosfomycin resistance in clinical isolates of E. coli.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, Japan. sho_takahata@meiji.co.jp
authors.forename: Sho
authors.initials: S
authors.lastname: Takahata
authors.forename: Takashi
authors.initials: T
authors.lastname: Ida
authors.forename: Toru
authors.initials: T
authors.lastname: Hiraishi
authors.forename: Shiro
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Kazunori
authors.initials: K
authors.lastname: Maebashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Terada
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Muratani
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Chikara
authors.initials: C
authors.lastname: Nakahama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tomono
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000235:genetics; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D054643:INDEL Mutation; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D005578:Fosfomycin