Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB

Maria A. Schumacher, Kevin M. Piro, Weijun Xu, Sonja Hansen, Kim Lewis, Richard G. Brennan

Research output: Contribution to journalArticlepeer-review

233 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)396-401
Number of pages6
JournalScience
Volume323
Issue number5912
DOIs
StatePublished - Jan 16 2009
Externally publishedYes

ASJC Scopus subject areas

  • General

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