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

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

doi:10.1371/journal.ppat.1005585

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

Journal Article · Wed May 04 00:00:00 EDT 2016 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1005585· OSTI ID:1404968

Mann, Paul A. ^[1]; Müller, Anna ^[2]; Wolff, Kerstin A. ^[1]; Fischmann, Thierry ^[1]; Wang, Hao ^[1]; Reed, Patricia ^[3]; Hou, Yan ^[1]; Li, Wenjin ^[4]; Müller, Christa E. ^[4]; Xiao, Jianying ^[1]; Murgolo, Nicholas ^[1]; Sher, Xinwei ^[1]; Mayhood, Todd ^[1]; Sheth, Payal R. ^[1]; Mirza, Asra ^[1]; Labroli, Marc ^[1]; Xiao, Li ^[1]; McCoy, Mark ^[1]; Gill, Charles J. ^[1]; Pinho, Mariana G. ^[3] more »

Merck Research Labs, Kenilworth, NJ (United States)
Univ. of Bonn (Germany); German Centre for Infection Research (DZIF), Bonn (Germany)
Univ. Nova de Lisboa, Oeiras (Portugal)
Univ. of Bonn (Germany)
Univ. of Tubingen (Germany)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: European Research Council (ERC)

Grant/Contract Number:: ERC-2012-StG-310987

OSTI ID:: 1404968

Journal Information:: PLoS Pathogens, Vol. 12, Issue 5; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 27 works

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

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