title: Role of the CpxAR two-component signal transduction system in control of fosfomycin resistance and carbon substrate uptake.
abstract: Although fosfomycin is an old antibiotic, it has resurfaced with particular interest. The antibiotic is still effective against many pathogens that are resistant to other commonly used antibiotics. We have found that fosfomycin resistance of enterohemorrhagic Escherichia coli (EHEC) O157:H7 is controlled by the bacterial two-component signal transduction system CpxAR. A cpxA mutant lacking its phosphatase activity results in constitutive activation of its cognate response regulator, CpxR, and fosfomycin resistance. We have shown that fosfomycin resistance requires CpxR because deletion of the cpxR gene in the cpxA mutant restores fosfomycin sensitivity. We have also shown that CpxR directly represses the expression of two genes, glpT and uhpT, which encode transporters that cotransport fosfomycin with their native substrates glycerol-3-phosphate and glucose-6-phosphate, and repression of these genes leads to a decrease in fosfomycin transport into the cpxA mutant. However, the cpxA mutant had an impaired growth phenotype when cultured with glycerol-3-phosphate or glucose-6-phosphate as a sole carbon substrate and was outcompeted by the parent strain, even in nutrient-rich medium. This suggests a trade-off between fosfomycin resistance and the biological fitness associated with carbon substrate uptake. We propose a role for the CpxAR system in the reversible control of fosfomycin resistance. This may be a beneficial strategy for bacteria to relieve the fitness burden that results from fosfomycin resistance in the absence of fosfomycin.
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kurabayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hirakawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Tomita
authors.forename: Hidetada
authors.initials: H
authors.lastname: Hirakawa
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D024881:Drug Resistance, Bacterial; D019453:Escherichia coli O157 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005578:Fosfomycin / Q000378:metabolism*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D026901:Membrane Transport Proteins / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D029968:Escherichia coli Proteins; C488962:GlpT protein, E coli; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D050505:Mutant Proteins; C063498:UhpT protein, E coli; C085504:CpxR protein, Bacteria; D005578:Fosfomycin; D002244:Carbon; D011494:Protein Kinases; C490475:CpxA protein, E coli; D010744:Phosphoric Monoester Hydrolases