ArticlePLoS pathogens2016
Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- Structure-based computational investigation of potential TarA inhibitors in Staphylococcus aureus.Molecular diversity · 2026Article
- Gram-negative-staining Bacillaceae with thick cell wall and monoderm architecture uncover evolutionary diversity and challenge Gram-based classification.Communications biology · 2026Article
- Bicarbonate Within: A Hidden Modulator of Antibiotic Susceptibility.Antibiotics (Basel, Switzerland) · 2025Review
- Synergistic potential of LeuBMC microbiology · 2024Article
- The MraY Inhibitor Muraymycin D2 and Its Derivatives Induce Enlarged Cells in Obligate IntracellularAntibiotics (Basel, Switzerland) · 2024Article
- Sensitizing methicillin-resistantAntimicrobial agents and chemotherapy · 2024Article
- Insights into structure and activity of a UDP-GlcNAc 2-epimerase involved in secondary cell wall polymer biosynthesis inFrontiers in molecular biosciences · 2024Article
- Structural analysis of a bacterial UDP-sugar 2-epimerase reveals the active site architecture before and after catalysis.The Journal of biological chemistry · 2023Article
- Secreted mammalian DNases protect against systemic bacterial infection by digesting biofilms.The Journal of experimental medicine · 2023Article
- The Emergence of a Multidrug-Resistant and Pathogenic ST42 Lineage of Staphylococcus haemolyticus from a Hospital in China.Microbiology spectrum · 2022Article
- Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria.Microorganisms · 2022Review
- Breaking down the cell wall: Still an attractive antibacterial strategy.Frontiers in microbiology · 2022Review
- Article
- Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition.Chemical Society reviews · 2021Review
- LcpB Is a Pyrophosphatase Responsible for Wall Teichoic Acid Synthesis and Virulence inFrontiers in microbiology · 2021Article
- Structural characterization of a nonhydrolyzing UDP-GlcNAc 2-epimerase from Neisseria meningitidis serogroup A.Acta crystallographica. Section F, Structural biology communications · 2020Article
- Tet38 of Staphylococcus aureus Binds to Host Cell Receptor Complex CD36-Toll-Like Receptor 2 and Protects from Teichoic Acid Synthesis Inhibitors Tunicamycin and Congo Red.Infection and immunity · 2019Article
- Interplay of Klebsiella pneumoniaemSphere · 2018Article
- Cationic Branched Polyethylenimine (BPEI) Disables Antibiotic Resistance in Methicillin-Resistant Staphylococcus epidermidis (MRSE).ChemMedChem · 2018Article
- Analysis of the Tunicamycin Biosynthetic Gene Cluster of Streptomyces chartreusis Reveals New Insights into Tunicamycin Production and Immunity.Antimicrobial agents and chemotherapy · 2018Article
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Authors and funding
22 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.