Using Chemical Reaction Kinetics to Predict Optimal Antibiotic Treatment Strategies
Fig 2
Delay to onset of antibiotic action depends on turnover rate and target occupancy at MIC.
(A) A definition of the MIC based on physicochemical characteristics. This graph shows the expected MIC in mol/L (based on Eq (3), y-axis) as a function of target occupancy at MIC (fc, x-axis). The colors indicate different affinities of drug target binding (KD). Blue: KD = 10−7 M, yellow: KD = 10−6 M, green: KD = 10−5 M. (B) This graph illustrates the time course of drug-target reaction (based on Eq (4)) for various parameter sets and a fixed antibiotic concentration just above MIC (1.01 x MIC). Dotted lines: Slow turnover rate of antibiotic-target binding with half-life of drug-target complex tbound = 1h 55 min (kr = 10−4). Solid lines: Fast turnover rate of antibiotic-target binding with half-life of drug-target complex tbound = 11.5 min (kr = 10−3). The colors indicate different target occupancies at MIC. Red: fc = 90%, Dark blue: fc = 50%, Yellow: fc = 10%. The grey lines at 90%, 50% and 10% indicate the fc, the threshold of bound target required to kill/inactivate the cell. The light blue solid and dotted vertical lines indicate when the fast and slow reactions reach the fc, i.e. the time of onset of the antibiotic action (tonset).