GMP-Cor: Quantifying Transcriptional Dysregulation in Antibiotic Tolerance and Persistence

When cells are exposed to stress, they typically activate stress-response pathways and enter a regulated growth-arrest. But what if the stress overwhelms these pathways? In such cases, cells may enter a disrupted growth-arrest - a poorly adapted, abrupt cessation of growth, characterized by a broad distribution of lag times upon stress removal. This distribution underlies antibiotic persistence during stress recovery. Therefore, gaining a deeper understanding of the disrupted growth-arrest is important for developing more effective antibiotic therapies. In this study, we perform single cell RNA-seq on bacteria in disrupted conditions. We develop GMP-Cor: a metric to quantify dysregulation and analyze gene-gene correlation patterns in sparse single-cell data. We find that gene-gene correlations are significantly reduced in disrupted cells compared to regulated cells, providing direct evidence that this tolerance-enhanced state, along with its increased membrane sensitivity, is associated with global-dysregulation. We demonstrate that GMP-Cor can extend to other biological systems, such as persistent cancer cells, where it separates proliferating from drug-arrested cells.

Gutfreund, A., Rotem, A., Ronin, I., Rosenthal, A. Z., Agam, O., Balaban, N. Q.

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