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Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif

A Brkic1, M Leibundgut2, J Jablonska3

  • 1Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000, Zagreb, Croatia.

Nature Communications
|September 7, 2023
PubMed

Insights

Antibiotic resistance in bacteria is a growing concern. This study reveals how altering a key enzyme motif (HIGH motif) in isoleucyl-tRNA synthetase (IleRS) can dramatically increase bacterial resistance to the antibiotic mupirocin.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Microbiology

Background:

  • Antibiotics are crucial for treating bacterial infections, but their overuse leads to rapid development of antibiotic resistance.
  • Mupirocin is a natural antibiotic that targets isoleucyl-tRNA synthetase (IleRS), an enzyme essential for protein synthesis.
  • Bacteria possess two forms of IleRS: a sensitive form (IleRS1) and a resistant form (IleRS2), which can be found in resistant clinical isolates like Staphylococcus aureus.

Purpose of the Study:

  • To elucidate the structural basis of mupirocin resistance in bacteria.
  • To uncover the mechanism behind hyper-resistance evolved by certain IleRS2 proteins.
  • To understand the coevolution of catalytic motifs and antibiotic resistance.

Main Methods:

  • Structural analysis of IleRS enzymes.
  • Investigating the role of the HIGH motif in antibiotic resistance.
  • Comparative analysis of mupirocin-sensitive (IleRS1) and resistant (IleRS2) forms.

Main Results:

  • A significant increase (up to 10^3-fold) in mupirocin resistance is linked to alterations in the HIGH motif of IleRS.
  • The structural analysis shows that IleRS2 can accommodate these HIGH motif alterations, unlike IleRS1.
  • This provides a structural explanation for evolved hyper-resistance.

Conclusions:

  • Alterations in the HIGH motif are a key mechanism for developing high-level mupirocin resistance in bacteria.
  • IleRS2's ability to adopt these altered motifs explains its role in clinical resistance.
  • The findings offer insights into the coevolution of essential enzymatic motifs and antibiotic resistance strategies.

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