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

In Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral membrane glycosyltransferase, attaches a formylated form of aminoarabinose to the lipid undecaprenyl phosphate, enabling its association with the bacterial inner membrane. Here, we present cryo-electron microscopy structures of ArnC from S. enterica in apo and nucleotide-bound conformations. These structures reveal a conformational transition that takes place upon binding of the partial donor substrate. Using coarse-grained and atomistic simulations, we provide insights into substrate coordination before and during catalysis, and we propose a catalytic mechanism that may operate on all similar metal-dependent polyprenyl phosphate glycosyltransferases. The reported structures provide a new target for drug design aiming to combat polymyxin resistance.

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Publication Details

Journal
Nature Communications
Published
2025-12-09
DOI
https://doi.org/10.1038/s41467-025-65968-6
Citations
1
Primary Topic
Antibiotic Resistance in Bacteria
Type
article
Field-Weighted Citation Impact
0.59

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article

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

Khuram U. Ashraf, Stephannie Rosario-Garrido, T. Bertie Ansell, Ankita Punetha et al.
1 citations
Nature Communications
Antibiotic Resistance in Bacteria
0.59
article

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

Khuram U. Ashraf, Stephannie Rosario-Garrido, T. Bertie Ansell, Ankita Punetha, Phillip J. Stansfeld, Emre Firlar, Mariana Batista, Vasileios I. Petrou, Jason T. Kaelber
article en
1 citations

Abstract

In Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral membrane glycosyltransferase, attaches a formylated form of aminoarabinose to the lipid undecaprenyl phosphate, enabling its association with the bacterial inner membrane. Here, we present cryo-electron microscopy structures of ArnC from S. enterica in apo and nucleotide-bound conformations. These structures reveal a conformational transition that takes place upon binding of the partial donor substrate. Using coarse-grained and atomistic simulations, we provide insights into substrate coordination before and during catalysis, and we propose a catalytic mechanism that may operate on all similar metal-dependent polyprenyl phosphate glycosyltransferases. The reported structures provide a new target for drug design aiming to combat polymyxin resistance.

Nature CommunicationsVol. 16(1)
Rutgers, The State University of New Jersey (US), SLAC National Accelerator Laboratory (US), University of Warwick (GB), University of Oxford (GB), Bristol-Myers Squibb (Belgium) (BE), Rutgers New Jersey Medical School (US)
University of Warwick, National Institutes of Health, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council
Openalex Percentile: Top 27%
Antibiotic Resistance in Bacteria
0.59
DOIOpen Access PDFOpenAlex
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