Evolution of Bacterial Tolerance Under Antibiotic Treatment and Its Implications on the Development of Resistance

Abstract

Recent laboratory evolution studies have shown that upon repetitive antibiotic treatments, bacterial populations will adapt and eventually became tolerant and resistant to the drug. Drug tolerance rapidly evolves upon frequent, intermittent antibiotic treatments, and such emerging drug tolerance seems to be specific to the treatment conditions, complicating clinical practice. Moreover, it has been shown that tolerance often promotes the development of resistance, which further reinforces the need of clinical diagnostics for antibiotic tolerance to reduce the occurrence of acquired resistance. Here, we discuss the laboratory evolution studies that were performed to track the development of tolerance in bacterial populations, and highlight the urgency of developing a comprehensive knowledge base of various tolerance phenotypes and their detection in clinics. Finally, we propose future directions for basic research in this growing field.

Keywords: antibiotic; laboratory evolution; persistence; resistance; tolerance.

FIGURE 1

Tolerance and resistance development during antibiotic treatment and regrowth. Typical evolution of bacterial populations under repetitive antibiotic treatments. When treated with high doses of bactericidal antibiotics, biphasic killing is observed where the susceptible cells die rapidly while the persisters survive prolonged treatments. After a few treatment and regrowth cycles, mutations that increase tolerance or persistence fraction may occur (blue outline on the cells), leading to higher overall survival of the population and a higher minimum duration of killing (blue line) toward the antibiotic. Over more treatment cycles, the bacteria may eventually attain mutations that govern resistance to the antibiotic (green diagonal stripes on the cells). Once the MIC of the population (green line) exceeds the dose of the antibiotic used during the treatment (green dotted line), the population can grow within the treatment regime and the antibiotic is no longer effective. MIC, minimum inhibitory concentration. MDK, minimum duration of killing.