| Summary: | The emergence of antibiotic tolerance enables genetically susceptible bacteria to withstand the killing by clinically relevant antibiotics. As is reported, an increasing body of evidence sheds light on the critical and underappreciated role of antibiotic tolerance in the disease burden of bacterial infections. Considering this tense situation, new therapeutic strategies are urgently required for combating antibiotic tolerance. Herein, we provide an insightful illustration to distinguish between antibiotic resistance and tolerance, and highlight its clinical significance and complexities of drug-tolerant bacteria. Then, we discuss the close relationship between antibiotic tolerance and bacterial metabolism. As such, a bacterial metabolism-based approach was proposed to counter antibiotic tolerance. These exogenous metabolites including amino acids, tricarboxylic acid cycle (TCA cycle) metabolites, and nucleotides effectively activate bacterial metabolism and convert the tolerant cells to sensitive cells, and eventually restore antibiotic efficacy. A better understanding of molecular mechanisms of antibiotic tolerance particularly in vivo would substantially drive the development of novel strategies targeting bacterial metabolism.
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