Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance

Structure. 2017 May 2;25(5):750-761.e5. doi: 10.1016/j.str.2017.03.007. Epub 2017 Apr 13.


The macrolides are a class of antibiotic, characterized by a large macrocyclic lactone ring that can be inactivated by macrolide phosphotransferase enzymes. We present structures for MPH(2')-I and MPH(2')-II in the apo state, and in complex with GTP analogs and six different macrolides. These represent the first structures from the two main classes of macrolide phosphotransferases. The structures show that the enzymes are related to the aminoglycoside phosphotransferases, but are distinguished from them by the presence of a large interdomain linker that contributes to an expanded antibiotic binding pocket. This pocket is largely hydrophobic, with a negatively charged patch located at a conserved aspartate residue, rationalizing the broad-spectrum resistance conferred by the enzymes. Complementary mutation studies provide insights into factors governing substrate specificity. A comparison with macrolides bound to their natural target, the 50S ribosome, suggests avenues for next-generation antibiotic development.

Keywords: antibiotic; drug; enzyme; kinase; macrolide; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteria / drug effects
  • Bacteria / enzymology
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Drug Resistance, Bacterial*
  • Guanosine Triphosphate / chemistry
  • Guanosine Triphosphate / metabolism
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Binding
  • Substrate Specificity


  • Bacterial Proteins
  • Macrolides
  • Guanosine Triphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • macrolide 2'-kinase