Regulatory Dynamics Determine Cell Fate following Abrupt Antibiotic Exposure

Bacterial resistance mechanisms must cope with transient fast-changing conditions. These systems are often repressed in the absence of the drug, and it is unclear how their regulation can provide a quick response when challenged. Here, we focus on the tet operon, which provides resistance to tetracycline through efflux pump TetA. We show that, somewhat counterintuitively, prompt expression of the TetA repressor TetR is key for cellular survival upon abrupt drug exposure. Tracking individual cells upon exposure, we find that differences in the rate of TetR elevation result in three distinct cell fates: recovery (high rate), death due to excess TetA (intermediate rate), and death from the drug (low rate). A surge of TetR expression optimizes the response by allowing sensitive detection of both the initial rise and the later decline of intracellular drug, avoiding an undesirable overshoot in TetA expression. These results show how regulatory circuits of resistance genes have evolved for optimized dynamics. Schultz et al. show that the tet resistance mechanism optimizes the dynamics of the response by quickly elevating expression of repressor TetR upon antibiotic exposure. This assures sensitivity not only to the presence of the drug but also to a decline in drug concentration, thus preventing unnecessary and toxic expression of the efflux pump, TetA.