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HipBA-promoter structures reveal the basis of heritable multidrug tolerance

Maria A Schumacher1, Pooja Balani2, Jungki Min1

  • 1Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA.

Nature
|July 30, 2015
PubMed

Insights

Multidrug tolerance in chronic infections stems from dormant persister cells. New research reveals how HipA protein dimerization controls this antibiotic tolerance, offering insights into urinary tract infections.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Genetics

Background:

  • Multidrug tolerance, often caused by dormant persister cells, is a major factor in chronic infections.
  • The Escherichia coli hipA gene was the first genetic link identified to multidrug tolerance.

Purpose of the Study:

  • To elucidate the physiological role of the HipA protein in multidrug tolerance.
  • To understand the mechanism behind high-persister mutations in hipA and their clinical relevance.

Main Methods:

  • Investigated wild-type and mutant HipA protein function in persister formation.
  • Utilized structural biology to determine the mechanism of HipA-HipB-promoter complex formation.
  • Analyzed high-persister mutations in relation to HipA structure and dimerization.

Main Results:

  • Wild-type HipA contributes to persister cell formation.
  • High-persister hipA mutants were found to cause multidrug tolerance in urinary tract infections.
  • HipA forms dimers via N-subdomain-1 interactions, occluding its active site; mutations disrupt this dimerization, enhancing tolerance.

Conclusions:

  • HipA protein dimerization is a key mechanism regulating multidrug tolerance.
  • Disruption of HipA dimerization by specific mutations underlies clinically relevant antibiotic tolerance.
  • This provides a mechanistic basis for heritable antibiotic tolerance in bacteria.

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