Abstract

Bacterial persistence, where a small subpopulation of cells (persister cells) enters a dormant state while the majority (normal cells) remain metabolically active, provides a survival strategy and fitness advantage in environments fluctuating between growth and antibiotic conditions. Recent studies have shown that drug accumulation in persister cells is significantly altered compared to that in normal cells. For β-lactam antibiotics, the efflux rate was found higher in E. coli persisters, leading to increased survival under antibiotic conditions. Conversely, for the antibiotic minocycline, a lower efflux rate results in higher drug accumulation but an increased death rate when cells switch to normally growing states. In both cases, drug accumulation in cells is stochastic in nature. Motivated by these experimental findings, we developed a stochastic model for drug accumulation in single cells exhibiting phenotype switching between normal and persister states. Our simulation results indicate that the distribution of drugs in cells depends on the rate of switching between cellular states and other parameters such as influx and efflux rates, leading to transitions between bimodal and unimodal distributions. Furthermore, we provide analytical expressions for the probability distribution, mean, and variance of the accumulated antibiotic as functions of different model parameters. Our theoretical results can be used to infer molecular parameters from the concentration distribution of various proteins, accumulated either through direct translation or via transport from the external environment.

BioSketch

Dr. Patra is an Assistant Professor in the Department of Physics at the Indian Institute of Technology Kharagpur, India. His research group focuses on theoretical biological physics and computational active matter. Dr. Patra completed his Ph.D. in Theoretical Biological Physics at the Max Planck Institute of Colloids and Interfaces in Germany, under the guidance of Prof. Stefan Klumpp, where he investigated the population dynamics of bacterial persistence. After completing his Ph.D., Dr. Patra joined as a postdoctoral researcher in the group of Prof. Oleg Igoshin in the Bio-engineering Department at Rice University, where he developed computational models to gain insights into the mechanisms behind the colony expansion of Myxobacteria. He later worked as a postdoc with Prof. Ulrich Schwarz at Heidelberg University, funded by the Cell Networks and SFB1129 programs, focusing on the collective migration of malaria parasites and malaria infection in red blood cells. Before joining his current position, Dr. Patra briefly worked in industry as a scientist specializing in image data analysis at Resolve BioSciences GmbH.