Role of the Multidrug Resistance Regulator MarA in Global Regulation of the hdeAB Acid Resistance Operon in Escherichia coli

Center for Adaptation Genetics and Drug Resistance and the Departments of Molecular Biology and Microbiology and of Medicine, Tufts University School of Medicine, Boston, MA 02111

^* To whom correspondence should be addressed. Email: stuart.levy{at}tufts.edu.

	Abstract

MarA, a transcriptional regulator in Escherichia coli, affects functions such as multiple antibiotic resistance (Mar) and virulence. Usually an activator, MarA is a repressor of hdeAB and other acid resistance genes. We found that, in wild-type cells grown in LB medium at pH 7.0 or pH 5.5, repression of hdeAB by MarA occurred only in stationary phase and was less in the absence of H-NS and GadE, the main regulators of hdeAB. Moreover, repression of hdeAB by MarA was greater in the absence of GadX or Lrp in exponential phase at pH 7.0, and in the absence of GadW or RpoS in stationary phase at pH 5.5. In turn, MarA enhanced repression of hdeAB by H-NS and hindered activation by GadE in stationary phase, as well as reduced the activity of GadX, GadW, RpoS and Lrp on hdeAB under some conditions. As a result of its direct and indirect effects, overexpression of MarA prevented most of the induction of hdeAB expression as cells enter stationary phase and made the cells 7-fold more sensitive to acid challenge at pH 2.5. These findings show that repression of hdeAB by MarA depends on pH, growth phase, and other regulators of hdeAB, and is associated with reduced resistance to acid conditions.