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Research Article | Spotlight

c-di-AMP Accumulation Impairs Muropeptide Synthesis in Listeria monocytogenes

Steven M. Massa, Amar Deep Sharma, Cheta Siletti, Zepeng Tu, Jared J. Godfrey, William G. Gutheil, TuAnh N. Huynh
Michael J. Federle, Editor
Steven M. Massa
aFood Science Department, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Amar Deep Sharma
bDivision of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri—Kansas City, Kansas City, Missouri, USA
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Cheta Siletti
cMicrobiology Doctoral Training Program, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Zepeng Tu
aFood Science Department, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Jared J. Godfrey
aFood Science Department, University of Wisconsin—Madison, Madison, Wisconsin, USA
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William G. Gutheil
bDivision of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri—Kansas City, Kansas City, Missouri, USA
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TuAnh N. Huynh
aFood Science Department, University of Wisconsin—Madison, Madison, Wisconsin, USA
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  • ORCID record for TuAnh N. Huynh
Michael J. Federle
University of Illinois at Chicago
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DOI: 10.1128/JB.00307-20
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ABSTRACT

Cyclic di-AMP (c-di-AMP) is an essential and ubiquitous second messenger among bacteria. c-di-AMP regulates many cellular pathways through direct binding to several molecular targets in bacterial cells. c-di-AMP depletion is well known to destabilize the bacterial cell wall, resulting in increased bacteriolysis and enhanced susceptibility to cell wall targeting antibiotics. Using the human pathogen Listeria monocytogenes as a model, we found that c-di-AMP accumulation also impaired cell envelope integrity. An L. monocytogenes mutant deleted for c-di-AMP phosphodiesterases (pdeA pgpH mutant) exhibited a 4-fold increase in c-di-AMP levels and several cell wall defects. For instance, the pdeA pgpH mutant was defective for the synthesis of peptidoglycan muropeptides and was susceptible to cell wall-targeting antimicrobials. Among different muropeptide precursors, we found that the pdeA pgpH strain was particularly impaired in the synthesis of d-Ala–d-Ala, which is required to complete the pentapeptide stem associated with UDP–N-acetylmuramic acid (MurNAc). This was consistent with an increased sensitivity to d-cycloserine, which inhibits the d-alanine branch of peptidoglycan synthesis. Finally, upon examining d-Ala:d-Ala ligase (Ddl), which catalyzes the conversion of d-Ala to d-Ala–d-Ala, we found that its activity was activated by K+. Based on previous reports that c-di-AMP inhibits K+ uptake, we propose that c-di-AMP accumulation impairs peptidoglycan synthesis, partially through the deprivation of cytoplasmic K+ levels, which are required for cell wall-synthetic enzymes.

IMPORTANCE The bacterial second messenger c-di-AMP is produced by a large number of bacteria and conditionally essential to many species. Conversely, c-di-AMP accumulation is also toxic to bacterial physiology and pathogenesis, but its mechanisms are largely undefined. We found that in Listeria monocytogenes, elevated c-di-AMP levels diminished muropeptide synthesis and increased susceptibility to cell wall-targeting antimicrobials. Cell wall defects might be an important mechanism for attenuated virulence in bacteria with high c-di-AMP levels.

FOOTNOTES

    • Received 22 May 2020.
    • Accepted 17 September 2020.
    • Accepted manuscript posted online 5 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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c-di-AMP Accumulation Impairs Muropeptide Synthesis in Listeria monocytogenes
Steven M. Massa, Amar Deep Sharma, Cheta Siletti, Zepeng Tu, Jared J. Godfrey, William G. Gutheil, TuAnh N. Huynh
Journal of Bacteriology Nov 2020, 202 (24) e00307-20; DOI: 10.1128/JB.00307-20

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c-di-AMP Accumulation Impairs Muropeptide Synthesis in Listeria monocytogenes
Steven M. Massa, Amar Deep Sharma, Cheta Siletti, Zepeng Tu, Jared J. Godfrey, William G. Gutheil, TuAnh N. Huynh
Journal of Bacteriology Nov 2020, 202 (24) e00307-20; DOI: 10.1128/JB.00307-20
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KEYWORDS

Listeria monocytogenes
c-di-AMP
peptidoglycan

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