ABSTRACT Despite the growing rate of worldwide antibiotic-resistant bacteria, introducing a new antibiotic to the market is significantly disappointing. A promising approach to control resistance is antibiotic combination. In the current study, a molecular network-based approach is developed to find activated/inactivated ATP-Binding Cassette (ABC) transporters in order to arrange a reasonable combination of antibiotics that is useful to inhibit the multidrug-resistant bacteria. To study the possibility of the antibiotic combination, RNA-seq analysis was performed on Escherichia coli ST131 treated by ciprofloxacin. Eight transporting systems were extracted from the differentially expressed genes including maltose, D/L methionine, spermidine, lipopolysaccharide, lipoprotein, macrolide, L-glutamine, and cystine ABC transporters (effluxes). Bacterial exposure to ciprofloxacin, as a typical fluoroquinolone, leads to the activation of the first four and inactivation of the last four effluxes. Among all inactivated effluxes, macAB-TolC ABC transporter is specifically responsible for expelling the macrolide antibiotics, e.g. erythromycin, and it seems that the combination of ciprofloxacin with erythromycin can overcome the resistance to the macrolide class of antibiotics.

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