Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Escherichia coli toxin gene hipA affects biofilm formation and DNA release.
J. Zhao, Q. Wang, M. Li, B. D. Heijstra, S. Wang, Q. Liang, and Q. Qi (2013)
Microbiology 159, 633-640
   Abstract »    Full Text »    PDF »
Isolation of Highly Persistent Mutants of Salmonella enterica Serovar Typhimurium Reveals a New Toxin-Antitoxin Module.
A. Slattery, A. H. Victorsen, A. Brown, K. Hillman, and G. J. Phillips (2013)
J. Bacteriol. 195, 647-657
   Abstract »    Full Text »    PDF »
Comparative Analysis of Mobilizable Genomic Islands.
A. Daccord, D. Ceccarelli, S. Rodrigue, and V. Burrus (2013)
J. Bacteriol. 195, 606-614
   Abstract »    Full Text »    PDF »
Hsp33 Controls Elongation Factor-Tu Stability and Allows Escherichia coli Growth in the Absence of the Major DnaK and Trigger Factor Chaperones.
N. Bruel, M.-P. Castanie-Cornet, A.-M. Cirinesi, G. Koningstein, C. Georgopoulos, J. Luirink, and P. Genevaux (2012)
J. Biol. Chem. 287, 44435-44446
   Abstract »    Full Text »    PDF »
Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many.
W. T. Chan, I. Moreno-Cordoba, C. C. Yeo, and M. Espinosa (2012)
Microbiol. Mol. Biol. Rev. 76, 773-791
   Abstract »    Full Text »    PDF »
Role of Oxidative Stress in Persister Tolerance.
Y. Wu, M. Vulic, I. Keren, and K. Lewis (2012)
Antimicrob. Agents Chemother. 56, 4922-4926
   Abstract »    Full Text »    PDF »
Global Expression Profile of Biofilm Resistance to Antimicrobial Compounds in the Plant-Pathogenic Bacterium Xylella fastidiosa Reveals Evidence of Persister Cells.
L. S. Muranaka, M. A. Takita, J. C. Olivato, L. T. Kishi, and A. A. de Souza (2012)
J. Bacteriol. 194, 4561-4569
   Abstract »    Full Text »    PDF »
Large mutational target size for rapid emergence of bacterial persistence.
H. S. Girgis, K. Harris, and S. Tavazoie (2012)
PNAS 109, 12740-12745
   Abstract »    Full Text »    PDF »
Fresh Approaches to Anti-Infective Therapies.
C. Nathan (2012)
Science Translational Medicine 4, 140sr2
   Full Text »    PDF »
Secreted Kinase Phosphorylates Extracellular Proteins That Regulate Biomineralization.
V. S. Tagliabracci, J. L. Engel, J. Wen, S. E. Wiley, C. A. Worby, L. N. Kinch, J. Xiao, N. V. Grishin, and J. E. Dixon (2012)
Science 336, 1150-1153
   Abstract »    Full Text »    PDF »
Molecular Structure and Function of the Novel BrnT/BrnA Toxin-Antitoxin System of Brucella abortus.
B. E. Heaton, J. Herrou, A. E. Blackwell, V. H. Wysocki, and S. Crosson (2012)
J. Biol. Chem. 287, 12098-12110
   Abstract »    Full Text »    PDF »
Crystal structure of the DNA-bound VapBC2 antitoxin/toxin pair from Rickettsia felis.
M. J. Mate, R. Vincentelli, N. Foos, D. Raoult, C. Cambillau, and M. Ortiz-Lombardia (2012)
Nucleic Acids Res. 40, 3245-3258
   Abstract »    Full Text »    PDF »
Toxin-Antitoxin Systems of Mycobacterium smegmatis Are Essential for Cell Survival.
R. Frampton, R. B. M. Aggio, S. G. Villas-Boas, V. L. Arcus, and G. M. Cook (2012)
J. Biol. Chem. 287, 5340-5356
   Abstract »    Full Text »    PDF »
Selective Killing of Bacterial Persisters by a Single Chemical Compound without Affecting Normal Antibiotic-Sensitive Cells.
J.-S. Kim, P. Heo, T.-J. Yang, K.-S. Lee, D.-H. Cho, B. T. Kim, J.-H. Suh, H.-J. Lim, D. Shin, S.-K. Kim, et al. (2011)
Antimicrob. Agents Chemother. 55, 5380-5383
   Abstract »    Full Text »    PDF »
Bacterial persistence by RNA endonucleases.
E. Maisonneuve, L. J. Shakespeare, M. G. Jorgensen, and K. Gerdes (2011)
PNAS 108, 13206-13211
   Abstract »    Full Text »    PDF »
Age of Inoculum Strongly Influences Persister Frequency and Can Mask Effects of Mutations Implicated in Altered Persistence.
H. Luidalepp, A. Joers, N. Kaldalu, and T. Tenson (2011)
J. Bacteriol. 193, 3598-3605
   Abstract »    Full Text »    PDF »
Diversity of bacterial type II toxin-antitoxin systems: a comprehensive search and functional analysis of novel families.
R. Leplae, D. Geeraerts, R. Hallez, J. Guglielmini, P. Dreze, and L. Van Melderen (2011)
Nucleic Acids Res. 39, 5513-5525
   Abstract »    Full Text »    PDF »
Characterization and Transcriptome Analysis of Mycobacterium tuberculosis Persisters.
I. Keren, S. Minami, E. Rubin, and K. Lewis (2011)
mBio 2, e00100-11
   Abstract »    Full Text »    PDF »
Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies.
M. Fauvart, V. N. De Groote, and J. Michiels (2011)
J. Med. Microbiol. 60, 699-709
   Abstract »    Full Text »    PDF »
Eukaryote-Like Serine/Threonine Kinases and Phosphatases in Bacteria.
S. F. F. Pereira, L. Goss, and J. Dworkin (2011)
Microbiol. Mol. Biol. Rev. 75, 192-212
   Abstract »    Full Text »    PDF »
Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance.
V. N. De Groote, M. Fauvart, C. I. Kint, N. Verstraeten, A. Jans, P. Cornelis, and J. Michiels (2011)
J. Med. Microbiol. 60, 329-336
   Abstract »    Full Text »    PDF »
The Structure and Interactions of SpoIISA and SpoIISB, a Toxin-Antitoxin System in Bacillus subtilis.
P. Florek, V. M. Levdikov, E. Blagova, A. A. Lebedev, R. Skrabana, S. Resetarova, P. Pavelcikova, I. Barak, and A. J. Wilkinson (2011)
J. Biol. Chem. 286, 6808-6819
   Abstract »    Full Text »    PDF »
Structure of the Escherichia coli Antitoxin MqsA (YgiT/b3021) Bound to Its Gene Promoter Reveals Extensive Domain Rearrangements and the Specificity of Transcriptional Regulation.
B. L. Brown, T. K. Wood, W. Peti, and R. Page (2011)
J. Biol. Chem. 286, 2285-2296
   Abstract »    Full Text »    PDF »
The PIN-domain ribonucleases and the prokaryotic VapBC toxin-antitoxin array.
V. L. Arcus, J. L. McKenzie, J. Robson, and G. M. Cook (2011)
Protein Eng. Des. Sel. 24, 33-40
   Abstract »    Full Text »    PDF »
Vibrio cholerae ParE2 Poisons DNA Gyrase via a Mechanism Distinct from Other Gyrase Inhibitors.
J. Yuan, Y. Sterckx, L. A. Mitchenall, A. Maxwell, R. Loris, and M. K. Waldor (2010)
J. Biol. Chem. 285, 40397-40408
   Abstract »    Full Text »    PDF »
Helicobacter pylori proinflammatory protein up-regulates NF-{kappa}B as a cell-translocating Ser/Thr kinase.
D. J. Kim, K.-S. Park, J.-H. Kim, S.-H. Yang, J. Y. Yoon, B.-G. Han, H. S. Kim, S. J. Lee, J. Y. Jang, K. H. Kim, et al. (2010)
PNAS 107, 21418-21423
   Abstract »    Full Text »    PDF »
Emergence of Pseudomonas aeruginosa Strains Producing High Levels of Persister Cells in Patients with Cystic Fibrosis.
L. R. Mulcahy, J. L. Burns, S. Lory, and K. Lewis (2010)
J. Bacteriol. 192, 6191-6199
   Abstract »    Full Text »    PDF »
European clinical isolate of Proteus mirabilis harbouring the Salmonella genomic island 1 variant SGI1-O.
B. Doublet, L. Poirel, K. Praud, P. Nordmann, and A. Cloeckaert (2010)
J. Antimicrob. Chemother. 65, 2260-2262
   Full Text »    PDF »
Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence.
E. Rotem, A. Loinger, I. Ronin, I. Levin-Reisman, C. Gabay, N. Shoresh, O. Biham, and N. Q. Balaban (2010)
PNAS 107, 12541-12546
   Abstract »    Full Text »    PDF »
The Escherichia coli mqsR and ygiT Genes Encode a New Toxin-Antitoxin Pair.
V. Kasari, K. Kurg, T. Margus, T. Tenson, and N. Kaldalu (2010)
J. Bacteriol. 192, 2908-2919
   Abstract »    Full Text »    PDF »
Patients with Long-Term Oral Carriage Harbor High-Persister Mutants of Candida albicans.
M. D. LaFleur, Q. Qi, and K. Lewis (2010)
Antimicrob. Agents Chemother. 54, 39-44
   Abstract »    Full Text »    PDF »
Bacterial Toxin HigB Associates with Ribosomes and Mediates Translation-dependent mRNA Cleavage at A-rich Sites.
J. M. Hurley and N. A. Woychik (2009)
J. Biol. Chem. 284, 18605-18613
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882