Tradeoffs in bacterial physiology determine the efficiency of antibiotic killing.

Abstract

Antibiotic effectiveness depends on a variety of factors. While many mechanistic details of antibiotic action are known, the connection between death rate and bacterial physiology is poorly understood. A common observation is that death rate in antibiotics rises linearly with growth rate; however, it remains unclear how other factors, such as environmental conditions and whole-cell physiological properties, affect bactericidal activity. To address this, we developed a high-throughput assay to precisely measure antibiotic-mediated death. We found that death rate is linear in growth rate, but the slope depends on environmental conditions. Growth under stress lowers death rate compared to nonstressed environments with similar growth rate. To understand stress's role, we developed a mathematical model of bacterial death based on resource allocation that includes a stress-response sector; we identify this sector using RNA-seq. Our model accurately predicts the minimal inhibitory concentration (MIC) with zero free parameters across a wide range of growth conditions. The model also quantitatively predicts death and MIC when sectors are experimentally modulated using cyclic adenosine monophosphate (cAMP), including protection from death at very low cAMP levels. The present study shows that different conditions with equal growth rate can have different death rates and establishes a quantitative relation between growth, death, and MIC that suggests approaches to improve antibiotic efficacy.