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Title: Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets

Abstract

Here we describe a chemical biology strategy performed in Staphylococcus aureus and Staphylococcus epidermidis to identify MnaA, a 2-epimerase that we demonstrate interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation of mnaA results in complete loss of WTA and dramatic in vitro β-lactam hypersensitivity in methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE). Likewise, the β-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA and MRSE infection. Interestingly, whereas MnaA serves as the sole 2-epimerase required for WTA biosynthesis in S. epidermidis, MnaA and Cap5P provide compensatory WTA functional roles in S. aureus. We also demonstrate that MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA and MRSE. We further determine the 1.9Å crystal structure of S. aureus MnaA and identify critical residues for enzymatic dimerization, stability, and substrate binding. Finally, the natural product antibiotic tunicamycin is shown to physically bind MnaA and Cap5P and inhibit 2-epimerase activity, demonstrating that it inhibits a previously unanticipated step in WTA biosynthesis. In summary, MnaA serves as a newmore » Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore β-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [1];  [4];  [4];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [3] more »;  [4];  [1];  [5] « less
+ Show Author Affiliations
  1. Merck Research Labs, Kenilworth, NJ (United States)
  2. Univ. of Bonn (Germany); German Centre for Infection Research (DZIF), Bonn (Germany)
  3. Univ. Nova de Lisboa, Oeiras (Portugal)
  4. Univ. of Bonn (Germany)
  5. Univ. of Tubingen (Germany)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
European Research Council (ERC)
OSTI Identifier:
1404968
Grant/Contract Number:  
ERC-2012-StG-310987
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 12; Journal Issue: 5; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; methicillin-resistant Staphylococcus aureus; biofilms; biosynthesis; Staphylococcus aureus; bacterial biofilms; Staphylococcus epidermidis; antibiotics; Staphylococcus

Citation Formats

Mann, Paul A., Müller, Anna, Wolff, Kerstin A., Fischmann, Thierry, Wang, Hao, Reed, Patricia, Hou, Yan, Li, Wenjin, Müller, Christa E., Xiao, Jianying, Murgolo, Nicholas, Sher, Xinwei, Mayhood, Todd, Sheth, Payal R., Mirza, Asra, Labroli, Marc, Xiao, Li, McCoy, Mark, Gill, Charles J., Pinho, Mariana G., Schneider, Tanja, Roemer, Terry, and Peschel, Andreas. Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets. United States: N. p., 2016. Web. doi:10.1371/journal.ppat.1005585.
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Mann, Paul A., Müller, Anna, Wolff, Kerstin A., Fischmann, Thierry, Wang, Hao, Reed, Patricia, Hou, Yan, Li, Wenjin, Müller, Christa E., Xiao, Jianying, Murgolo, Nicholas, Sher, Xinwei, Mayhood, Todd, Sheth, Payal R., Mirza, Asra, Labroli, Marc, Xiao, Li, McCoy, Mark, Gill, Charles J., Pinho, Mariana G., Schneider, Tanja, Roemer, Terry, & Peschel, Andreas. Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets. United States. https://doi.org/10.1371/journal.ppat.1005585
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Mann, Paul A., Müller, Anna, Wolff, Kerstin A., Fischmann, Thierry, Wang, Hao, Reed, Patricia, Hou, Yan, Li, Wenjin, Müller, Christa E., Xiao, Jianying, Murgolo, Nicholas, Sher, Xinwei, Mayhood, Todd, Sheth, Payal R., Mirza, Asra, Labroli, Marc, Xiao, Li, McCoy, Mark, Gill, Charles J., Pinho, Mariana G., Schneider, Tanja, Roemer, Terry, and Peschel, Andreas. Wed . "Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets". United States. https://doi.org/10.1371/journal.ppat.1005585. https://www.osti.gov/servlets/purl/1404968.
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@article{osti_1404968,
title = {Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets},
author = {Mann, Paul A. and Müller, Anna and Wolff, Kerstin A. and Fischmann, Thierry and Wang, Hao and Reed, Patricia and Hou, Yan and Li, Wenjin and Müller, Christa E. and Xiao, Jianying and Murgolo, Nicholas and Sher, Xinwei and Mayhood, Todd and Sheth, Payal R. and Mirza, Asra and Labroli, Marc and Xiao, Li and McCoy, Mark and Gill, Charles J. and Pinho, Mariana G. and Schneider, Tanja and Roemer, Terry and Peschel, Andreas},
abstractNote = {Here we describe a chemical biology strategy performed in Staphylococcus aureus and Staphylococcus epidermidis to identify MnaA, a 2-epimerase that we demonstrate interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation of mnaA results in complete loss of WTA and dramatic in vitro β-lactam hypersensitivity in methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE). Likewise, the β-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA and MRSE infection. Interestingly, whereas MnaA serves as the sole 2-epimerase required for WTA biosynthesis in S. epidermidis, MnaA and Cap5P provide compensatory WTA functional roles in S. aureus. We also demonstrate that MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA and MRSE. We further determine the 1.9Å crystal structure of S. aureus MnaA and identify critical residues for enzymatic dimerization, stability, and substrate binding. Finally, the natural product antibiotic tunicamycin is shown to physically bind MnaA and Cap5P and inhibit 2-epimerase activity, demonstrating that it inhibits a previously unanticipated step in WTA biosynthesis. In summary, MnaA serves as a new Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore β-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation.},
doi = {10.1371/journal.ppat.1005585},
journal = {PLoS Pathogens},
number = 5,
volume = 12,
place = {United States},
year = {Wed May 04 00:00:00 EDT 2016},
month = {Wed May 04 00:00:00 EDT 2016}
}
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Factors influencing methicillin resistance in staphylococci
journal, September 2002

Biosynthesis of the unit that links teichoic acid to the bacterial wall: Inhibition by tunicamycin
journal, October 1976

A Revised Pathway Proposed for Staphylococcus aureus Wall Teichoic Acid Biosynthesis Based on In Vitro Reconstitution of the Intracellular Steps
journal, January 2008

Chemical Genetic Identification of Peptidoglycan Inhibitors Potentiating Carbapenem Activity against Methicillin-Resistant Staphylococcus aureus
journal, August 2009

Antagonism of Chemical Genetic Interaction Networks Resensitize MRSA to β-Lactam Antibiotics
journal, November 2011

Discovery of Wall Teichoic Acid Inhibitors as Potential Anti-MRSA β-Lactam Combination Agents
journal, February 2013

The wall teichoic acid and lipoteichoic acid polymers of Staphylococcus aureus
journal, February 2010

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Pathways and roles of wall teichoic acid glycosylation in Staphylococcus aureus
journal, May 2014

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Are essential genes really essential?
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Synthetic Lethal Compound Combinations Reveal a Fundamental Connection between Wall Teichoic Acid and Peptidoglycan Biosyntheses in Staphylococcus aureus
journal, November 2010

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  • ACS Chemical Biology, Vol. 6, Issue 1
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ABC Transporters Required for Export of Wall Teichoic Acids Do Not Discriminate between Different Main Chain Polymers
journal, February 2011

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Inhibition of WTA Synthesis Blocks the Cooperative Action of PBPs and Sensitizes MRSA to β-Lactams
journal, October 2012

  • Farha, Maya A.; Leung, Alexander; Sewell, Edward W.
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Discovery of Novel Putative Inhibitors of UDP-GlcNAc 2-Epimerase as Potent Antibacterial Agents
journal, October 2013

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  • ACS Medicinal Chemistry Letters, Vol. 4, Issue 12
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Distinct and essential morphogenic functions for wall- and lipo-teichoic acids in Bacillus subtilis
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A structural basis for the allosteric regulation of non‐hydrolysing UDP‐GlcNAc 2‐epimerases
journal, November 2008

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Taking aim at wall teichoic acid synthesis: new biology and new leads for antibiotics
journal, October 2013

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  • The Journal of Antibiotics, Vol. 67, Issue 1
  • DOI: 10.1038/ja.2013.100

Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions
journal, March 2008

  • Weidenmaier, Christopher; Peschel, Andreas
  • Nature Reviews Microbiology, Vol. 6, Issue 4
  • DOI: 10.1038/nrmicro1861

The Challenge of Treating Biofilm-associated Bacterial Infections
journal, May 2007

Recent developments and applications of saturation transfer difference nuclear magnetic resonance (STD NMR) spectroscopy
journal, January 2013

  • Wagstaff, Jane L.; Taylor, Samantha L.; Howard, Mark J.
  • Mol. BioSyst., Vol. 9, Issue 4
  • DOI: 10.1039/c2mb25395j

Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus
journal, May 2007

  • Grundling, A.; Schneewind, O.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 20
  • DOI: 10.1073/pnas.0701821104

Teichoic acids are temporal and spatial regulators of peptidoglycan cross-linking in Staphylococcus aureus
journal, October 2010

  • Atilano, M. L.; Pereira, P. M.; Yates, J.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 44
  • DOI: 10.1073/pnas.1004304107

Methicillin resistance in Staphylococcus aureus requires glycosylated wall teichoic acids
journal, October 2012

  • Brown, S.; Xia, G.; Luhachack, L. G.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 46
  • DOI: 10.1073/pnas.1209126109

Compound-gene interaction mapping reveals distinct roles for Staphylococcus aureus teichoic acids
journal, August 2014

  • Santa Maria, J. P.; Sadaka, A.; Moussa, S. H.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 34
  • DOI: 10.1073/pnas.1404099111

Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase
journal, August 2015

  • Farha, Maya A.; Czarny, Tomasz L.; Myers, Cullen L.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 35
  • DOI: 10.1073/pnas.1511751112

An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci
journal, August 2001

  • Pinho, M. G.; de Lencastre, H.; Tomasz, A.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 19
  • DOI: 10.1073/pnas.191260798

Lack of Wall Teichoic Acids in Staphylococcus aureus Leads to Reduced Interactions with Endothelial Cells and to Attenuated Virulence in a Rabbit Model of Endocarditis
journal, May 2005

  • Weidenmaier, Christopher; Peschel, Andreas; Xiong, Yan‐Qiong
  • The Journal of Infectious Diseases, Vol. 191, Issue 10
  • DOI: 10.1086/429692

Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America
journal, January 2009

  • Boucher, Helen W.; Talbot, George H.; Bradley, John S.
  • Clinical Infectious Diseases, Vol. 48, Issue 1
  • DOI: 10.1086/595011

Penetration of antibiotics through Staphylococcus aureus and Staphylococcus epidermidis biofilms
journal, July 2010

  • Singh, R.; Ray, P.; Das, A.
  • Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 9
  • DOI: 10.1093/jac/dkq257

Methicillin-resistant Staphylococcus aureus: the European landscape
journal, April 2011

  • Johnson, A. P.
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  • DOI: 10.1093/jac/dkr076

Wall teichoic acid protects Staphylococcus aureus from inhibition by Congo red and other dyes
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Biofilm resistance to antimicrobial agents
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Wall teichoic acids are dispensable for anchoring the PNAG exopolysaccharide to the Staphylococcus aureus cell surface
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Device-Related Infection Among Patients With Pacemakers and Implantable Defibrillators: Incidence, Risk Factors, and Consequences
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Restoring Methicillin-Resistant Staphylococcus aureus Susceptibility to  -Lactam Antibiotics
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TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci
journal, March 2016

Staphylococcus aureus PBP4 Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant Strains
journal, August 2008

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Molecular Basis and Phenotype of Methicillin Resistance in Staphylococcus aureus and Insights into New β-Lactams That Meet the Challenge
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Dual Roles of FmtA in Staphylococcus aureus Cell Wall Biosynthesis and Autolysis
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Key Role of Teichoic Acid Net Charge inStaphylococcus aureus Colonization of Artificial Surfaces
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Duplication of Teichoic Acid Biosynthetic Genes in Staphylococcus aureus Leads to Functionally Redundant Poly(Ribitol Phosphate) Polymerases
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The N-Acetylmannosamine Transferase Catalyzes the First Committed Step of Teichoic Acid Assembly in Bacillus subtilis and Staphylococcus aureus
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Wall Teichoic Acid Polymers Are Dispensable for Cell Viability in Bacillus subtilis
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GneZ, a UDP-GlcNAc 2-Epimerase, Is Required for S-Layer Assembly and Vegetative Growth of Bacillus anthracis
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Cloning and characterization of a gene affecting the methicillin resistance level and the autolysis rate in Staphylococcus aureus.
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Staphylococcus aureus cap5P Encodes a UDP- N -Acetylglucosamine 2-Epimerase with Functional Redundancy
journal, August 1999

Ratio of Teichoic Acid and Peptidoglycan in Cell Walls of Bacillus subtilis Following Spore Germination and During Vegetative Growth
journal, January 1968

Persister Cells
journal, October 2010

Use of a Bacteriophage Lysin to Identify a Novel Target for Antimicrobial Development
journal, April 2013

Harnessing the power of transposon mutagenesis for antibacterial target identification and evaluation
journal, July 2012

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