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Role of Histone-Like Protein H-NS in Multidrug Resistance of Escherichia coli

Department of Bacterial Infections, Research Institute for Microbial Diseases,¹ Faculty of Pharmaceutical Science, Osaka University, Suita, Osaka 565-0871,⁴ Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki,² Core Research Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Osaka 567-0047, Japan³

Received 22 August 2003/ Accepted 14 November 2003

The histone-like protein H-NS is a major component of the bacterial nucleoid and plays a crucial role in global gene regulation of enteric bacteria. It is known that the expression of a variety of genes is repressed by H-NS, and mutations in hns result in various phenotypes, but the role of H-NS in the drug resistance of Escherichia coli has not been known. Here we present data showing that H-NS contributes to multidrug resistance by regulating the expression of multidrug exporter genes. Deletion of the hns gene from the acrAB mutant increased levels of resistance against antibiotics, antiseptics, dyes, and detergents. Decreased accumulation of ethidium bromide and rhodamine 6G in the hns mutant compared to that in the parental strain was observed, suggesting the increased expression of some drug exporter(s) in this mutant. The increased drug resistance and decreased drug accumulation caused by the hns deletion were completely suppressed by deletion of the multifunctional outer membrane channel gene tolC. At least eight drug exporter systems require TolC for their functions. Among these, increased expression of acrEF, mdtEF, and emrKY was observed in the hns strain by quantitative real-time reverse transcription-PCR analysis. The hns-mediated multidrug resistance pattern is quite similar to that caused by overproduction of the AcrEF exporter. Deletion of the acrEF gene greatly suppressed the level of hns-mediated multidrug resistance. However, this strain still retained resistance to some compounds. The remainder of the multidrug resistance pattern was similar to that conferred by overproduction of the MdtEF exporter. Double deletion of the mdtEF and acrEF genes completely suppressed hns-mediated multidrug resistance, indicating that hns-mediated multidrug resistance is due to derepression of the acrEF and mdtEF drug exporter genes.

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