Inhibition of the staphylococcal pyruvate dehydrogenase multi-enzyme complex by a new class of antibiotics

  • Timo Birkenstock, University of Tuebingen, Germany
  • Manuel Liebeke, University of Greifswald, Germany
  • Hans Bisswanger, University of Greifswald, Germany
  • Martin Koeberle, University of Tuebingen, Germany
  • Erwin Bohn, University of Tuebingen, Germany
  • Andrea Schnell, Gambro Dialysatoren GmbH, Hechingen, Germany
  • Reinhold Deppisch, Gambro Dialysatoren GmbH, Hechingen, Germany
  • Andreas Peschel, University of Tuebingen, Germany
  • Michael Lalk, University of Greifswald, Germany

    • Here we identify a novel lead substance with potent antibacterial activity against Gram-positive bacteria. The compound is highly efficient against isolates that are resistant to antibiotics commonly used in the hospital suggesting a novel antimicrobial mechanism. Using an NMR-based metabolomics approach, we identify the staphylococcal pyruvate-dehydrogenase multi-enzyme complex (PDHC), the key-enzyme fuelling the bacterial tri-carbon cycle, as the major molecular target of the substance. Inhibition of the bacterial PDHC results in the accumulation of pyruvate and the induction of pyruvate-utilizing fermentation pathways. This induces growth-arrest and ultimately results in death of the bacterium presumably due to depletion of cellular reducing power. The identification of this novel antimicrobial lead substance and its molecular target site might pave the way towards an efficient strategy for the eradication of antibiotic resistant staphylococci.