Many Chromosomal Genes Modulate MarA-Mediated Multidrug Resistance in Escherichia coli

ABSTRACT Multidrug resistance (MDR) in clinical isolates of Escherichia coli can be associated with overexpression of marA , a transcription factor that upregulates multidrug efflux and downregulates membrane permeability. Using random transposome mutagenesis, we found that many chromosomal genes and environmental stimuli affected MarA-mediated antibiotic resistance. Seven genes affected resistance mediated by MarA in an antibiotic-specific way; these were mostly genes encoding unrelated enzymes, transporters, and unknown proteins. Other genes affected MarA-mediated resistance to all antibiotics tested. These genes were acrA , acrB , and tolC (which encode the major MarA-regulated multidrug efflux pump AcrAB-TolC), crp , cyaA , hns , and pcnB (four genes involved in global regulation of gene expression), and the unknown gene damX . The last five genes affected MarA-mediated MDR by altering marA expression or MarA function specifically on acrA . These findings demonstrate that MarA-mediated MDR is regulated at multiple levels by different genes and stimuli, which makes it both complex and fine-tuned and interconnects it with global cell regulation and metabolism. Such a regulation could contribute to the adaptation and spread of MDR strains and may be targeted to treat antibiotic-resistant E. coli and related pathogens.