Enhanced disinfection of bacterial populations by nutrient and antibiotic challenge timing.

Several difficult to treat illnesses like tuberculosis, chronic pneumonia, and inner ear infections are caused by tolerant bacteria enmeshed in a biofilm. Bacterial tolerance can be genotypic (resistance-i.e. MRSA), phenotypic (non-heritable) or environmental (e.g. nutrient gradients). Persister formation is a phenotypic expression and this phenotype is highly tolerant of disinfection. Constant dosing is typically ineffective and to generate an effective treatment protocol, we need to understand the dynamics of persister cells. In this study, we investigate how manipulating the application of antibiotics and addition of nutrients enhances the disinfection of a bacterial population in batch culture. Eliminating persister bacteria is considered as a challenge for the food industry or wastewater treatment, since the failure may result in food contamination and disease transmission. Previous studies focused on the antimicrobial agent as a control variable to eliminate the bacterial population. In addition to antibiotic, we consider the significance of the nutrient in eradicating the susceptible and persister cells since the disinfection of susceptible population depends on the nutrient intake. We present a mathematical model that captures the dynamics between susceptible and persister bacteria with antibiotic and nutrient control variables. We investigate the optimal dose-withdrawal of antibiotic timing in several cases including constant nutrient in time, dynamic nutrient in time and piecewise constant nutrient in time.