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Updated: May 27, 2025

Generation of Null Mutants to Elucidate the Role of Bacterial Glycosyltransferases in Bacterial Motility
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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

  • 1Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical Health Sciences, Newark, NJ, 07103, USA.

Biorxiv : the Preprint Server for Biology
|February 20, 2025
PubMed

Insights

Researchers elucidated the structure of ArnC, a key enzyme in bacterial polymyxin resistance. Understanding its mechanism offers new avenues for developing drugs to combat antibiotic resistance.

Area of Science:

  • Microbiology
  • Structural Biology
  • Biochemistry

Background:

  • Lipid A modification with aminoarabinose (L-Ara4N) in Gram-negative bacteria confers resistance to polymyxins.
  • ArnC is an integral membrane glycosyltransferase essential for L-Ara4N transfer to lipid-II-P.
  • Polymyxin resistance is a growing global health concern.

Purpose of the Study:

  • To determine the structural basis of ArnC function.
  • To elucidate the mechanism of aminoarabinose transfer by ArnC.
  • To identify potential targets for novel antimicrobial drug development.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to obtain high-resolution structures of ArnC.
  • Molecular simulations (coarse-grained and atomistic) were employed to study substrate binding and catalysis.
  • Biochemical assays were used to validate the proposed catalytic mechanism.

Main Results:

  • Structures of ArnC from *S. enterica* were determined in apo and nucleotide-bound states.
  • A conformational transition upon partial donor substrate binding was observed.
  • Simulations provided insights into substrate coordination and a proposed catalytic mechanism for polyprenyl phosphate glycosyltransferases.

Conclusions:

  • The structural and mechanistic insights into ArnC provide a foundation for rational drug design.
  • Targeting ArnC could be a viable strategy to overcome polymyxin resistance in Gram-negative bacteria.
  • This study contributes to understanding membrane-associated glycosyltransferases and antibiotic resistance mechanisms.
Keywords:
Polymyxin resistancePren-P GTaminoarabinoseglycosyltransferaselipopolysaccharidemembrane proteinundecaprenyl phosphate

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