Antibacterial agent 330

Antibacterialagent 330 is an antibacterial agent that accumulates reactive oxygen species (ROS), forms DNA supramolecular complexes to block DNA replication through intercalation, and inhibits lactate dehydrogenase (LDH) to disrupt metabolism. This process leads to bacterial cell rupture and intracellular content leakage, ultimately causing bacterial death. Antibacterialagent 330 has demonstrated antibacterial activity and promoted wound healing in both Galleria mellonella larvae and mouse wound infection models. It is suitable for research on bacterial infections.

Antibacterial agent 330 (Compound I-10b) exhibits significant inhibitory effects against various Gram-positive and Gram-negative bacterial strains, with minimum inhibitory concentrations (MICs) ranging from 0.0007 to 0.0026 mM, and demonstrates a minimum MIC of 0.0003 mM against Enterococcus faecalis, effectively inhibiting clinical isolates at low concentrations. Furthermore, agent 330 (4×-8× MIC; up to 8 h) shows concentration-dependent bactericidal activity against Staphylococcus aureus 25923 and Enterococcus faecalis, with a notable reduction in colony-forming units (CFU) within 6 hours at 8× MIC. It has a low potential to induce bacterial resistance in Staphylococcus aureus 25923 and Enterococcus faecalis over 14 days and strongly inhibits sulfamethoxazole-resistant strains at concentrations of 0.0007-0.0055 mM. With negligible hemolytic toxicity observed at 32×-64× MIC over 4 hours, it shows no significant cytotoxicity towards normal human LO2 liver cells and Beas-2b lung epithelial cells at concentrations of 5-40 μg/mL. Additionally, Antibacterial agent 330 effectively reduces and eliminates biofilms of Staphylococcus aureus 25923 and Enterococcus faecalis in a concentration-dependent manner, achieving over 40% clearance of Staphylococcus aureus 25923 biofilms at 16× MIC. It also increases the membrane permeability of both Staphylococcus aureus 25923 and Enterococcus faecalis at 1×-16× MIC and induces protein leakage in a concentration-dependent manner (0.5×-8× MIC), suggesting bacterial membrane disruption. The agent causes intracellular reactive oxygen species (ROS) accumulation in a concentration-dependent manner (0.5×-16× MIC) and inhibits the lactate dehydrogenase (LDH) activity of both Staphylococcus aureus 25923 and Enterococcus faecalis, with an inhibition rate of approximately 45% at 16× MIC.

Antibacterial agent 330 (Compound I-10b) administered at 0.007-0.014 mM [injection; single dose] exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus 25923) in Galleria mellonella larvae, with a survival rate of 90% at 0.007 mM and almost complete survival at 0.014 mM after 8 days. This compound, applied topically at 4× MIC [once daily for 6 days], effectively promotes wound healing in a mouse infection model while reducing the bacterial load of S. aureus 25923, without affecting normal weight gain. Additionally, at a dose of 5 mg/kg/day [daily administration for 3 consecutive days], it demonstrates good in vivo biosafety in Kunming mice, with no observed histopathological damage to major organs.