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

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...

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Published in:Scientific reports Vol. 8; no. 1; pp. 8708 - 15
Main Authors: Jatana, Samreen, Homer, Craig R., Madajka, Maria, Ponti, András K., Kabi, Amrita, Papay, Francis, McDonald, Christine
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 07-06-2018
Nature Publishing Group
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-27012-0