Population Density Modulates Drug Inhibition and Gives Rise to Potential Bistability of Treatment Outcomes for Bacterial Infections
A. Top row: Steady state population growth was measured as a function of cell density (here schematically represented by low, medium, and high density) by holding each vial at a constant density while exposing cells to constant drug concentration in highly buffered media. Bottom row: Different culture vials were all held at low-density (OD = 0.2) but grown in BHI supplemented with HCl to achieve pH = 7.5, 6.8, and 6.0, which correspond to pH of steady state cultures held at OD = 0.2, 0.5, and 0.8, respectively. B. Red curves, regular media. Black dashed curves, buffered media. Blue dotted curves, external pH modulation. Tigecycline concentration 50 ug/mL; Ampicillin concentration 200 ng/mL;C. Red curves, regular media. Black dashed curves, buffered media. Ciprofloxacin concentration 200 ng/mL, Spectinomycin concentration 150 ug/mL. Statistically significant differences between growth at lowest and highest densities (0.2 and 0.8), intermediate densities (0.4 and 0.6), or both are indicated by *, **, and ***, respectively. See also Figure D in S1 Text. Error bars are +/- 1.96 standard error (95% confidence intervals).