title: Cooperative Actions of CRP-cAMP and FNR Increase the Fosfomycin Susceptibility of EnterohaemorrhagicEscherichia coli(EHEC) by Elevating the Expression ofglpTanduhpTunder Anaerobic Conditions.
abstract: Bacterial infections to anaerobic site are often hard to be treated because the activity of most of antimicrobials decreases under anaerobic conditions. However, fosfomycin rather provides a greater activity under anaerobic conditions than aerobic conditions. Previously, we found that expression ofglpTanduhpT, fosfomycin symporters in enterohaemorrhagicEscherichia coli(EHEC) was upregulated by FNR, a global regulator during the anaerobiosis of the bacterium, which led to increased uptake and susceptibility to this drug. In this study, we showed that expression ofglpTanduhpTis induced by CRP-cAMP, the regulator complex under both aerobic and anaerobic conditions. The activity of CRP-cAMP in EHEC was elevated under anaerobic conditions because levels of both CRP and cAMP were higher in the cells when grown anaerobically than those when grown aerobically. Results of expression study using mutants indicated that CRP-cAMP is indispensable for expression ofglpTbut notuhpT-whereas that ofuhpTrequires UhpA that is the response regulator composing of two-component system with the sensor kinase, UhpB. The CRP-cAMP protein bound to a region that overlaps RNA polymerase binding site forglpTand region upstream of UhpA binding site foruhpT. FNR bound to a region further upstream of CRP-cAMP binding site on region upstream of theglpTgene. These combined results suggested that increased antibacterial activity of fosfomycin to EHEC under anaerobic conditions is due to activation of FNR and increment of CRP-cAMP activity. Then, FNR enhances the expression ofglpTactivated by CRP-cAMP while CRP-cAMP and FNR cooperatively aids the action of UhpA to expressuhpTto maximum level.
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Graduate School of Medicine, Gunma University Gunma, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kurabayashi
authors.affiliation: Laboratory of Bacterial Drug Resistance, Gunma University, Graduate School of Medicine Gunma, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Laboratory of Bacterial Drug Resistance, Gunma University, Graduate School of MedicineGunma, Japan; Department of Bacteriology, Gunma University, Graduate School of MedicineGunma, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Graduate School of Medicine, Gunma University Gunma, Japan.
authors.forename: Hidetada
authors.initials: H
authors.lastname: Hirakawa
keywords: anaerobiosis; catabolite repression; drug resistance; fosfomycin; transporter