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

• 成果类型: Article
• 署名作者: Parsons, Joshua B.; Sidders, Ashelyn E.; Velez, Amanda Z.; Hanson, Blake M.; Angeles-Solano, Michelle; Ruffin, Felicia; Rowe, Sarah E.; Arias, Cesar A.; Fowler, Vance G., Jr.; Thaden, Joshua T.; Conlon, Brian P.
• 署名单位: Duke University; University of North Carolina; University of North Carolina Chapel Hill; University of Texas System; University of Texas Health Science Center Houston; Houston Methodist; Houston Methodist; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9583
• DOI: 10.1073/pnas.2314514121
• 发表日期: 2024-01-16
• 关键词: tolerance; epidemiology; cells; bacteremia; resistance; physiology; RISK

摘要

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 Escherichia coli 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 E. coli 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 ptsI gene encoding Enzyme I of the phosphoenolpyruvate phosphotransferase system. The ptsI 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.