Infection and Drug Resistance (Mar 2024)

Inhibiting Peptidoglycan Hydrolase Alleviates MRSA Pneumonia Through Autolysin-Mediated MDP-NOD2 Pathway

  • Yang Y,
  • Yao Z,
  • Zhang J,
  • Shao W,
  • Li B,
  • Wu H,
  • Tang W,
  • Zhang J

Journal volume & issue
Vol. Volume 17
pp. 1231 – 1242

Abstract

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Yang Yang,1,2 Zongze Yao,1 Jiazhen Zhang,1 Wei Shao,3 Bo Li,2 Huihui Wu,2 Wenjian Tang,3 Jing Zhang2 1School of Medicine, Anhui University of Science and Technology, Huainan, People’s Republic of China; 2Anhui Province Key Laboratory of Occupational Health, Anhui No.2 Provincial People’s Hospital, Hefei, People’s Republic of China; 3School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Wenjian Tang; Jing Zhang, Tel +86-551-63672601, Email [email protected]; [email protected]: Methicillin-resistant Staphylococcus aureus (MRSA) is a cause of staph infection that is difficult to treat because of resistance to some antibiotics. A recent study indicated that diarylurea ZJ-2 is a novel antibacterial agent against multi-drug resistant Enterococcus faecium. In this work, we refined the bactericidal mechanism of ZJ-2 as a peptidoglycan (PG) hydrolase by affecting AtlA-mediated PG homeostasis.Methods: A wild-type strain (WT) and a mutant strain (ΔatlA) were used to investigate the effects of ZJ-2 on the cell wall, PG, and autolysin regulatory system by antimicrobial susceptibility testing, hemolytic toxin assay, microanalysis, autolysis assay, qRT-PCR, ELISA and mouse model of pneumonia.Results: The results revealed that ZJ-2 down-regulated the expression of genes related to peptidoglycan hydrolase (PGH) (sprX, walR, atlA, and lytM), and reduced the levels of PG, muramyl dipeptide (MDP), cytokines, and hemolytic toxin, while ΔatlA interfered with the genes regulation and PG homeostasis. In the mouse MRSA pneumonia model, the same trend was observed in the nucleotide oligomerization domain protein 2 (NOD2) and relative proinflammatory factors.Conclusion: ZJ-2 may act as a novel inhibitor of PG hydrolyse, disrupting autolysin-mediated PG homeostasis, and reducing inflammation by down-regulating the MDP-NOD2 pathway. Keywords: MRSA, peptidoglycan hydrolase, homeostasis, autolysis, NOD2

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