Molecular dynamics insight of novel Enzybiotic Salmcide-p1 lysis peptidoglycan to inhibit Salmonella Typhimurium

Salmcide-p1 is an enzybiotic derived from Salmonella bacteriophage fmb-p1 with broad-spectrum antibacterial activity against Gram-negative bacteria. This study found that Salmcide-p1 completely destroyed the structural integrity of Salmonella Typhimurium within 15 min, causing the leakage of intracellular nucleic acids, proteins, K+, and Ca2+, ultimately inducing cell apoptosis and necrosis. Meanwhile, Salmcide-p1 could lyse most of the Salmonella Typhimurium cell wall peptidoglycans within 1 h, and complete the lysis within 2 h. Therefore, the catalytic lysis of peptidoglycan is a key mechanism for Salmcide-p1 to inhibit Gram-negative bacteria. Furthermore, quantum chemical calculations of peptidoglycan from Gram-negative bacteria revealed that the glycosidic bond between N-acetylglucosamine and N-acetylmuramic acid is a potential site for catalytic lysis. All-atom molecular dynamics simulations revealed that the residues between Gly10 to His40 of Salmcide-p1 contributed the most to the binding free energy and the formation of hydrogen bonds between Salmcide-p1 and the cell wall peptidoglycan. The hydrophobic effect of the hydrophobic pocket of the beta-barrel domain of Salmcide-p1 played an important role in the binding of Salmcide-p1 to peptidoglycan. The beta-sheet of the beta-barrel domain was the catalytic active center, and Glu18 and Tyr25 were the key residues of Salmcide-p1 for the lysis of peptidoglycan. This work revealed the molecular dynamics mechanism of the interaction between Salmcide-p1 and bacterial peptidoglycan.

Automated summary

Salmcide-p1 is an enzybiotic derived from Salmonella bacteriophage fmb-p1 with broad-spectrum antibacterial activity against Gram-negative bacteria. This study revealed the mechanism of interaction between Salmcide-p1 and bacterial peptidoglycan, showing that catalytic lysis of peptidoglycan is a key mechanism for its inhibitory effect.