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Structural basis of undecaprenyl phosphate glycosylation leading to polymyxin resistance in Gram-negative bacteria

Khuram U Ashraf1,2, Mariana Bunoro-Batista3, T Bertie Ansell4,5

  • 1Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ, USA.

Nature Communications
|December 9, 2025
PubMed

Insights

Gram-negative bacteria resist polymyxins via Lipid A modification. Researchers determined the structure of ArnC, a key enzyme in this process, revealing a conformational change that could lead to new drug targets against antibiotic resistance.

Area of Science:

  • Microbiology
  • Biochemistry
  • Structural Biology

Background:

  • Lipid A modification with aminoarabinose (L-Ara4N) confers resistance in Gram-negative bacteria to polymyxin antibiotics.
  • ArnC is an integral membrane glycosyltransferase essential for L-Ara4N transfer to Lipid A.

Purpose of the Study:

  • To elucidate the structural basis of ArnC function and substrate binding.
  • To provide insights into the catalytic mechanism of ArnC.
  • To identify potential drug targets for combating polymyxin resistance.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine ArnC structures.
  • Molecular dynamics simulations (coarse-grained and atomistic) to study substrate coordination and dynamics.

Main Results:

  • Determined cryo-EM structures of S. enterica ArnC in apo and nucleotide-bound states.
  • Observed a significant conformational transition upon binding of the partial donor substrate.
  • Provided mechanistic insights into substrate coordination and catalysis.

Conclusions:

  • The structural and mechanistic insights into ArnC provide a foundation for developing novel inhibitors.
  • Targeting ArnC could be a viable strategy to overcome polymyxin resistance in Gram-negative bacteria.

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