Pyrimidine synthesis inhibition enhances cutaneous defenses against antibiotic resistant bacteria through activation of NOD2 signaling

Abstract

Multidrug-resistant bacterial strains are a rapidly emerging healthcare threat; therefore it is critical to develop new therapies to combat these organisms. Prior antibacterial strategies directly target pathogen growth or viability. Host-directed strategies to increase antimicrobial defenses may be an effective alternative to antibiotics and reduce development of resistant strains. In this study, we demonstrated the efficacy of a pyrimidine synthesis inhibitor, N-phosphonacetyl-l-aspartate (PALA), to enhance clearance of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Acinetobacter baumannii strains by primary human dermal fibroblasts in vitro. PALA did not have a direct bactericidal effect, but enhanced cellular secretion of the antimicrobial peptides human β-defensin 2 (HBD2) and HBD3 from fibroblasts. When tested in porcine and human skin explant models, a topical PALA formulation was efficacious to enhance MRSA, P. aeruginosa, and A. baumannii clearance. Topical PALA treatment of human skin explants also resulted in increased HBD2 and cathelicidin (LL-37) production. The antimicrobial actions of PALA required expression of nucleotide-binding, oligomerization domain 2 (NOD2), receptor-interacting serine/threonine-protein kinase 2 (RIP2), and carbamoyl phosphatase synthase II/aspartate transcarbamylase/dihydroorotase (CAD). Our results indicate that PALA may be a new option to combat multidrug-resistant bacterial infections of the skin through enhancement of an integral pathway of the cutaneous innate immune defense system.

Characterization of the circulating microbiome in acute‐on‐chronic liver failure associated with hepatitis B

“…In addition, bacteria may produce metabolites that regulate innate and adaptive immune responses . For example, methane, glutamate and pyrimidine, whose pathways were activated in HB‐ACLF, were reported to be regulators of innate or adaptive immune responses …”

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro

“…Besides the depletion of nucleotide pools for viral genome synthesis, blocking the pyrimidine synthesis was also demonstrated to activate the innate immune response by upregulation of interferon-inducible antiviral genes [8,9,54,55]. This indirect antiviral effect involving the interferon regulatory factor 1 (IRF1) transcription factor and induction of endogenous interferons to induce a broad host-mediated antiviral cellular state might additionally contribute to the antiviral activity of IMU-838 and other DHODH inhibitors [53,56].…”

Novel aroylated phenylenediamine compounds enhance antimicrobial defense and maintain airway epithelial barrier integrity

“…Another interesting approach was through the pattern recognition receptor NOD2 (Nucleotide Binding Oligomerization Domain Containing 2), when activation of this receptor by N-phosphonacetyl-L-aspartate (PALA), was identified as a potent inducer of innate immunity. Expression of HBD2 and CAMP were induced by PALA and antimicrobial activity was demonstrated in skin explants against bacteria including methicillin-resistant Staphylococcus aureus (MRSA) 48 .…”