New candidate anti MRSA drugs discovered by Shanghai Institute of medicine, Chinese Academy of Sciences

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common pathogens in community acquired infection and hospital acquired infection The mortality rate of the infected is 64% higher than that of the non resistant bacteria It is listed as a very serious resistant bacteria by the World Health Organization It calls for the development of new antibiotics for the treatment of MRSA infection Spirillyrinones are a new type of antibacterial compounds with new structure and new mechanism of action They have strong antibacterial activity against multidrug-resistant Gram-positive bacteria, especially fluoroquinolone resistant Gram-positive bacteria and multidrug-resistant Neisseria gonorrhoeae Azd0914 / etx0914 of AstraZeneca has made the fastest progress They are currently in II / III Stage clinical treatment of gonococcal infection With etx0914 as the lead compound, the research group of Yangyu society of Shanghai Institute of medicine finally selected 33E as the candidate drug through reasonable structure design, structure-activity relationship, structure-generation relationship, structure-toxicity relationship and drug-forming research 33E overcomes the shortcomings of etx0914, such as weak antibacterial activity, poor metabolic property and high toxicity It has a good development prospect 33E has a strong antibacterial activity against MRSA, PRSP, MRSE, etc., the minimum inhibitory solubility (MIC) is less than or equal to 0.03mg/l, significantly better than etx0914, and has a good antibacterial activity against 40 clinical isolates of Neisseria gonorrhoeae, MIC value is 0.015-0.5mg/l 33E also has excellent physical and chemical properties and metabolic properties In the metabolism experiment (10 MPK) of mice administered orally, auc0-t is 32 times higher than etx0914, and the half-life is longer In rats and dogs, 33E still showed good exposure and dose exposure relationship In the mouse model of MRSA infection, 33E showed significantly better antibacterial activity than etx0914, with ED50 of 3.87 mg / kg and 8.37 mg / kg, respectively The research results were recently published online in the Journal of pharmaceutical chemistry of the American Chemical Society (DOI: 10.1021 / ACS Jmedchem 8b01750) The first co authors are Shi Chenghui and Zhang Yinyong (Lian Peisheng), master's degree students, and Yang Yushe, researcher of Shanghai Institute of medicine, Chinese Academy of Sciences and Zhou Xianli, Professor of Southwest Jiaotong University The research work was independently deployed by Shanghai Pharmaceutical Research Institute and supported by national major new drug creation major special project.