GPR17 as an Innate Sensor for Bacterial Peptidoglycan: Implications for Necrotizing Fasciitis

Necrotizing fasciitis (NF) is a rapidly progressive, life-threatening infection of the fascial planes that disproportionately strikes otherwise healthy individuals, implying a dominant role for host genetic susceptibility. Here we present transcriptomic and structural pharmacophore evidence supporting GPR17, a G protein-coupled receptor with established responsiveness to uracil nucleotides, as a candidate surface-expressed pattern recognition receptor (PRR) for UDP-muramyl dipeptide (UDP-MDP) — a peptidoglycan fragment shed constitutively by both gram-positive and gram-negative bacteria. Reanalysis of Human Protein Atlas Single Cell RNA-seq data reveals that GPR17 is expressed predominantly on tissue macrophages (31.7 nTPM) and monocytes (12–18 nTPM), with markedly lower expression in lymphoid lineages (< 2 nTPM). Pharmacophore analysis using RDKit (v2023.9) demonstrates that the only validated synthetic GPR17 agonist, MDL29,951, shares a 15-atom maximum common substructure (MCS, 79% of MDL29,951) with indomethacin, a widely used NSAID. Both compounds contain the indole ring system, a carboxylate-bearing acetic acid sidechain, and a chloro substituent — suggesting that indomethacin may occupy the GPR17 binding pocket, potentially antagonizing UDP-MDP detection. This provides a structural basis for the clinically observed association between NSAID use and worsened NF outcomes. We additionally propose that the muramyl-dipeptide extension of UDP-MDP fulfills the full activation pharmacophore that UDP alone cannot, parsimoniously explaining prior negative UDP pharmacology data. These findings identify GPR17 as a priority candidate for whole-exome sequencing studies in NF case cohorts and implicate NSAID-mediated GPR17 inhibition as a modifiable risk factor.