title: Mechanism Underlying Time-dependent Cross-phenomenon between Concentration-response Curves and Concentration Addition Curves: A Case Study of Sulfonamides-Erythromycin mixtures on Escherichia coli.
abstract: Previous studies have identified a phenomenon in which the concentration-response curves (CRCs) for mixtures cross the curves for concentration addition model when predicting or judging joint toxic actions. However, mechanistic investigations of this phenomenon are extremely limited. In this study, a similar phenomenon was observed when we determined the joint toxic actions of sulfonamides (SAs) and erythromycin (ERY) on Escherichia coli (E. coli), which we named the "cross-phenomenon", and it was characterized by antagonism in the low-concentration range, addition in the medium-concentration range, and synergism in the high-concentration range. The mechanistic investigation of the cross-phenomenon was as follows: SAs and ERY could form a double block to inhibit the bacterial growth by exhibiting a synergistic effect; however, the hormetic effect of SAs on E. coli led to antagonism in the low-concentration range, resulting from the stimulation of sdiA mRNA expression by SAs, which increased the expression of the efflux pump (AcrAB-TolC) to discharge ERY. Furthermore, this cross-phenomenon was observed to be a time-dependent process induced by the increase of both the concentration and extent of stimulation of sdiA mRNA with exposure time. This work explains the dose-dependent and time-dependent cross-phenomenon and provides evidence regarding the interaction between hormesis and cross-phenomenon.
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China.|Collaborative Innovation Center for Regional Environmental Quality, China.
authors.forename: Zhifen
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Shanghai Key Laboratory of Chemical Assessment and Sustainability, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004926:Escherichia coli / Q000254:growth & development*; D029968:Escherichia coli Proteins / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D004917:Erythromycin; D029968:Escherichia coli Proteins; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013449:Sulfonamides; C083497:AcrA protein, E coli; C083496:AcrB protein, E coli; C073126:tolC protein, E coli