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Science 323 (5912): 396-401

Copyright © 2009 by the American Association for the Advancement of Science

Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB

Maria A. Schumacher,1* Kevin M. Piro,1 Weijun Xu,1 Sonja Hansen,2 Kim Lewis,2 Richard G. Brennan1*

Abstract: Bacterial multidrug tolerance is largely responsible for the inability of antibiotics to eradicate infections and is caused by a small population of dormant bacteria called persisters. HipA is a critical Escherichia coli persistence factor that is normally neutralized by HipB, a transcription repressor, which also regulates hipBA expression. Here, we report multiple structures of HipA and a HipA-HipB-DNA complex. HipA has a eukaryotic serine/threonine kinase–like fold and can phosphorylate the translation factor EF-Tu, suggesting a persistence mechanism via cell stasis. The HipA-HipB-DNA structure reveals the HipB-operator binding mechanism, ~70° DNA bending, and unexpected HipA-DNA contacts. Dimeric HipB interacts with two HipA molecules to inhibit its kinase activity through sequestration and conformational inactivation. Combined, these studies suggest mechanisms for HipA-mediated persistence and its neutralization by HipB.

1 Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Unit 1000, Houston, TX 77030, USA.
2 Department of Biology and Anti-microbial Discovery Center, Northeastern University, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: rgbrenna{at}mdanderson.org (R.G.B.); maschuma{at}mdanderson.org (M.A.S.)

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