Potentials of organic tellurium-containing compound AS101 to overcome carbapenemase-producing Escherichia coli

Abstract

Abstract Background: The issue of carbapenem-resistant Escherichia coli was aggravated yearly. The previous studies reported the varied but critical epidemiology of carbapenemresistant E. coli among which the carbapenemase-producing strains were regarded as one of the most notorious issues. AS101, an organic tellurium-containing compound undergoing clinical trials, was revealed with antibacterial activities. However, little is known about the antibacterial effect of AS101 against carbapenemase-producing E. coli (CPEC). Materials and methods: The minimum inhibitory concentration (MIC) of AS101 against the 15 isolates was examined using a broth microdilution method. The scanning electron microscopy, pharmaceutical manipulations, reactive oxygen species level, and DNA fragmentation assay were carried out to investigate the antibacterial mechanism. The sepsis mouse model was employed to assess the in vivo treatment effect. Results: The blaNDM (33.3%) was revealed as the dominant carbapenemase gene among the 15 CPEC isolates, followed by the blaKPC gene (26.7%). The MICs of AS101 against the 15 isolates ranged from 0.5 to 32 mg/ml, and 99.9% of bacterial eradication was observed at 8 h, 4 h, and 2 h for 1 , 2 , and 4 MIC, respectively. The mechanistic investigations suggest that AS101 would enter the bacterial cell, and induce ROS generation, leading to DNA fragmentation. The in vivo study exhibited that AS101 possessed a steady treatment effect in a sepsis mouse model, with an up to 83.3% of survival rate. Conclusion: The in vitro activities, mechanisms, and in vivo study of AS101 against CPEC were unveiled. Our finding provided further evidence for the antibiotic development of AS101.