Resuscitation dynamics reveal persister partitioning after antibiotic treatment

• Type of Material: Article
• Authors: Xin Fang, Emory University; Kyle Allison, Emory University
• Language: English
• Date: 2023-03-03
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published under the terms of the CC BY 4.0 license
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.15252/msb.202211320
• Title of Journal or Parent Work: MOLECULAR SYSTEMS BIOLOGY
• Volume: 19
• Issue: 4
• Start Page: e11320
• End Page: e11320
• Keywords: SURVIVAL; INHIBITION; PENICILLIN; Biochemistry & Molecular Biology; antibiotics; partitioning; resuscitation; ESCHERICHIA-COLI; Life Sciences & Biomedicine; TOLERANCE; persister; EVOLUTION; Science & Technology; CELL-DIVISION; dynamics; BACTERIAL PERSISTERS; INFECTIONS; PROTEINS
• Research Categories: Engineering, Biomedical

Abstract

Bacteria can survive antibiotics by forming dormant, drug-tolerant persisters. Persisters can resuscitate from dormancy after treatment and prolong infections. Resuscitation is thought to occur stochastically, but its transient, single-cell nature makes it difficult to investigate. We tracked the resuscitation of individual persisters by microscopy after ampicillin treatment and, by characterizing their dynamics, discovered that Escherichia coli and Salmonella enterica persisters resuscitate exponentially rather than stochastically. We demonstrated that the key parameters controlling resuscitation map to the ampicillin concentration during treatment and efflux during resuscitation. Consistently, we observed many persister progeny have structural defects and transcriptional responses indicative of cellular damage, for both β-lactam and quinolone antibiotics. During resuscitation, damaged persisters partition unevenly, generating both healthy daughter cells and defective ones. This persister partitioning phenomenon was observed in S. enterica, Klebsiella pneumoniae, Pseudomonas aeruginosa, and an E. coli urinary tract infection (UTI) isolate. It was also observed in the standard persister assay and after in situ treatment of a clinical UTI sample. This study reveals novel properties of resuscitation and indicates that persister partitioning may be a survival strategy in bacteria that lack genetic resistance.