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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.

plos pathogens

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