Methicillin-resistant Staphylococcus aureus (MRSA), as one of the most common pathogens in both community-acquired and hospital-acquired infections, is associated with a 64% higher mortality rate compared to non-drug-resistant bacterial infections. The World Health Organization has classified MRSA as a critically important antibiotic-resistant bacterium and has called for the development of novel antibiotics to treat MRSA infections.
Spiropyrimidinetrione compounds are a novel class of antibacterial agents with unique structures and mechanisms of action. They exhibit potent activity against multidrug-resistant Gram-positive bacteria, particularly fluoroquinolone-resistant Gram-positive strains, as well as multidrug-resistant Neisseria gonorrhoeae. The most advanced candidate in this class is AZD0914/ETX0914 from AstraZeneca, which is currently in Phase II/III clinical trials for the treatment of uncomplicated gonococcal infections. Led by Professor Yang Yushe at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the research team used ETX0914 as a lead compound. Through rational structural design, structure-activity relationship (SAR), structure-metabolism relationship (SMR), structure-toxicity relationship (STR), and druggability studies, they ultimately selected compound 33e as the drug candidate. Compound 33e overcomes the limitations of ETX0914, including moderate antibacterial potency, poor metabolic properties, and significant toxicity, demonstrating promising potential for further development.
Compound 33e exhibits potent antibacterial activity against MRSA, PRSP, and MRSE, with minimum inhibitory concentrations (MICs) ≤ 0.03 mg/L, significantly superior to ETX0914. It also demonstrates strong antibacterial activity against 40 clinical isolates of Neisseria gonorrhoeae, with MIC values ranging from 0.015 to 0.5 mg/L. Compound 33e possesses favorable physicochemical and metabolic properties. In a mouse oral pharmacokinetic study at a dose of 10 mg/kg, its AUC0–t was more than 32-fold higher than that of ETX0914 (24,241 h·ng/mL vs. 748 ± 215 h·ng/mL), and it exhibited a longer half-life (6.20 h vs. 3.41 h). In rats and dogs, compound 33e maintained good exposure and a clear dose-exposure relationship. In a murine MRSA infection model, compound 33e showed significantly superior in vivo antibacterial efficacy compared to the control drug ETX0914, with ED50 values of 3.87 mg/kg and 8.37 mg/kg, respectively.
The research findings were recently published online in the Journal of Medicinal Chemistry, a journal of the American Chemical Society. The co-first authors are master’s students Shi Chenghui and Zhang Yinyong (jointly trained student), under the supervision of Professor Yang Yushe, a researcher at the Shanghai Institute of Materia Medica, and Professor Zhou Xianli from Southwest Jiaotong University. This work was supported by the self-deployed projects of the Shanghai Institute of Materia Medica and the National Major Project for New Drug Development.