The antibacterial effect of tellurite is achieved through intracellular acidification and magnesium disruption.

Antibiotic resistance has caused a severe reduction in bacteriostatic action and clinical therapy, demanding effective agents or strategies. Tellurite is an ancient yet powerful antimicrobial agent with an ambiguous mechanism. In this study, we uncovered the underlying action mechanism of tellurite by disturbing the cellular homeostasis of proton and metal ions. Tellurite, entering into MG1655 cells, synchronously imported excess protons and induced intracellular acidification. The intracellular pH declined upon exposure to 0.5 μg/ml of tellurite (the minimal inhibitory concentration, MIC) for 15 min, decreasing from 7.5 to 6.3 in 3 h. A dramatic decrease (31%-73%) in cellular magnesium contents and cytoplastic Mg levels occured early after a 5-min treatment with tellurite, primarily via the enhanced efflux by FocB/MdtL/MdtG and the reduced influx by MgtA/CorA. Disruption of cellular Mg homeostasis by tellurite severely hindered ribosome assembly, retarded protein synthesis, and disturbed cellular metabolism. This action logic was applicable to various pathogens. Furthermore, a combination of trace tellurite (0.01/0.1× MIC) synergistically augmented the efficacy of antibiotics at sublethal doses (0.5× MIC) against hypervirulent and drug-resistant bacterial strains in vitro and in vivo, significantly enhancing the survival rate and the wound-healing rate of infected animals. These discoveries regarding this metalloid present a promising perspective for combating stubborn and drug-resistant pathogens.