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Related Experiment Videos

Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance.

Desiree H Fong1, David L Burk1, Jonathan Blanchet1

  • 1Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montréal, QC H3G 0B1, Canada.

Structure (London, England : 1993)
|April 19, 2017
PubMed
Summary

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Macrolide phosphotransferase enzymes, responsible for antibiotic resistance, were structurally characterized. These findings reveal insights into their broad-spectrum activity and potential for developing new antibiotics.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Microbiology

Background:

  • Macrolides are antibiotics with a large macrocyclic lactone ring.
  • Macrolide phosphotransferase (MPH) enzymes inactivate macrolide antibiotics.
  • MPH enzymes are a significant cause of antibiotic resistance.

Purpose of the Study:

  • To present the first structures of MPH(2')-I and MPH(2')-II enzymes.
  • To elucidate the structural basis for macrolide inactivation by MPH enzymes.
  • To identify potential targets for next-generation antibiotic development.

Main Methods:

  • X-ray crystallography was used to determine enzyme structures.
  • Structures were obtained for apo enzymes and complexes with GTP analogs and macrolides.
Keywords:
antibioticdrugenzymekinasemacrolideresistance

Related Experiment Videos

  • Site-directed mutagenesis was employed to study enzyme-substrate interactions.

    • Main Results:

    • Structures of MPH(2')-I and MPH(2')-II were determined in various states.
    • The enzymes share homology with aminoglycoside phosphotransferases but possess a unique interdomain linker.
    • A broad-spectrum antibiotic binding pocket with hydrophobic and charged regions was identified.

    Conclusions:

    • The determined structures provide a detailed understanding of macrolide inactivation mechanisms.
    • Enzyme structure rationalizes broad-spectrum antibiotic resistance.
    • Structural insights can guide the design of novel antibiotics to combat resistance.