In-patient evolution of a high-persister Escherichia coli strain with reduced in vivo antibiotic susceptibility

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 3; p. e2314514121
• Main Authors: Parsons, Joshua B, Sidders, Ashelyn E, Velez, Amanda Z, Hanson, Blake M, Angeles-Solano, Michelle, Ruffin, Felicia, Rowe, Sarah E, Arias, Cesar A, Fowler, Jr, Vance G, Thaden, Joshua T, Conlon, Brian P
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.01.2024
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Bacteremia; Bacteremia - drug therapy; Bacteria; Biological Sciences; E coli; Enzyme I; Escherichia coli; Escherichia coli - genetics; Health services; Humans; Infections; Mice; Mutants; Mutation; Patients; Phosphotransferase; PtsI gene; Recurrence; Sepsis; Survival; antibiotic; persistence; Escherichia coli; tolerance; bacteremia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2314514121

Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Despite appropriate antibiotic treatment, relapse of GNB-BSI with the same bacterial strain is common and associated with poor clinical outcomes and high healthcare costs. The role of persister cells, which are sub-populations of bacteria that survive for prolonged periods in the presence of bactericidal antibiotics, in relapse of GNB-BSI is unclear. Using a cohort of patients with relapsed GNB-BSI, we aimed to determine how the pathogen evolves within the patient between the initial and subsequent episodes of GNB-BSI and how these changes impact persistence. Using clinical bloodstream isolate pairs (initial and relapse isolates) from patients with relapsed GNB-BSI, we found that 4/11 (36%) of the relapse isolates displayed a significant increase in persisters cells relative to the initial bloodstream infection isolate. In the relapsed strain with the greatest increase in persisters (100-fold relative to initial isolate), we determined that the increase was due to a loss-of-function mutation in the gene encoding Enzyme I of the phosphoenolpyruvate phosphotransferase system. The mutant was equally virulent in a murine bacteremia infection model but exhibited 10-fold increased survival to antibiotic treatment. This work addresses the controversy regarding the clinical relevance of persister formation by providing compelling data that not only do high-persister mutations arise during bloodstream infection in humans but also that these mutants display increased survival to antibiotic challenge in vivo.