Drug detoxification dynamics explain the postantibiotic effect

• Published in: Molecular systems biology 2017-10, Vol.13 (10), p.948-n/a
• Main Authors: Srimani, Jaydeep K, Huang, Shuqiang, Lopatkin, Allison J, You, Lingchong
• Format: Article
• Language: English
• Subjects: Adjuvants; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; antibiotic tolerance; Antibiotics; Bacteria; Binding; Detoxification; Dynamics; Efflux; EMBO23; EMBO33; Empirical analysis; Escherichia coli - drug effects; Escherichia coli - growth & development; Escherichia coli - metabolism; Escherichia coli Proteins - metabolism; Inactivation, Metabolic; Inhibition; Mathematical models; Microfluidic Analytical Techniques; Microorganisms; Models, Theoretical; postantibiotic effect; systems biology; Titration
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20177723

The postantibiotic effect (PAE) refers to the temporary suppression of bacterial growth following transient antibiotic treatment. This effect has been observed for decades for a wide variety of antibiotics and microbial species. However, despite empirical observations, a mechanistic understanding of this phenomenon is lacking. Using a combination of modeling and quantitative experiments, we show that the PAE can be explained by the temporal dynamics of drug detoxification in individual cells after an antibiotic is removed from the extracellular environment. These dynamics are dictated by both the export of the antibiotic and the intracellular titration of the antibiotic by its target. This mechanism is generally applicable for antibiotics with different modes of action. We further show that efflux inhibition is effective against certain antibiotic motifs, which may help explain mixed cotreatment success. Synopsis The postantibiotic effect (PAE) refers to the temporary inhibition of bacterial growth following transient antibiotic treatment. This study indicates an underlying mechanism for this phenomenon, based on minimal binding and efflux dynamics. The PAE is a widely observed phenomenon whereby bacterial populations transiently exhibit minimal growth after temporary antibiotic treatment. In this study, mathematical modeling and experimental studies demonstrate that PAE can be explained by drug binding and efflux dynamics, and that these processes are applicable to many diverse antibiotics. Modeling analyses show that the efficacy of efflux pump inhibitors, widely thought to be effective antibiotic adjuvants, is modulated by mechanism‐dependent dynamics. Graphical Abstract The postantibiotic effect (PAE) refers to the temporary inhibition of bacterial growth following transient antibiotic treatment. This study indicates an underlying mechanism for this phenomenon, based on minimal binding and efflux dynamics.