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Evolution of Resistant Mutants in Pseudomonas aeruginosa Persister Cells Under Meropenem Treatment
Jie Feng1, Yifan Bian1, Congjuan Xu1
1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Abstract:
Bacterial persisters are dormant cells that survive antibiotic treatment, serving as a reservoir for the emergence of resistant mutations. The evolution of antibiotic resistance poses a significant challenge to public health. In this study, we investigated the development of resistance in Pseudomonas aeruginosa persister cells by exposing the reference strain PA14 to meropenem and tracked the emergence of resistance mutations over serial passages. Whole-genome sequencing of the populations or individual resistant strains revealed evolutionary trajectories. In the initial passages, low-level meropenem-resistant mutants harbored various mutations, accompanied by increasing population survival. Then, mutations in the oprD gene appeared, followed by mutation in the mexR gene in most of the cells, leading to high-level meropenem resistance and collateral resistance to ciprofloxacin. Our study provides insights into the evolutionary pathways of P. aeruginosa under lethal antibiotic pressure, highlighting the dynamic interplay between persister cells and the emergence of resistance mutations.
Insights
Bacterial persister cells in Pseudomonas aeruginosa can evolve high-level meropenem resistance through specific gene mutations, posing a public health challenge. Understanding these evolutionary pathways is crucial for combating antibiotic resistance.
Area of Science:
- Microbiology
- Evolutionary Biology
- Genetics
Background:
- Bacterial persisters are dormant cells that survive antibiotic treatment.
- Antibiotic resistance evolution is a major public health concern.
- Pseudomonas aeruginosa is an opportunistic pathogen known for developing resistance.
Purpose of the Study:
- To investigate the evolutionary pathways of antibiotic resistance development in Pseudomonas aeruginosa persister cells.
- To track the emergence and genetic basis of meropenem resistance in P. aeruginosa.
- To understand the role of persister cells in the evolution of resistance.
Main Methods:
- Exposure of P. aeruginosa strain PA14 to meropenem over serial passages.
- Whole-genome sequencing of resistant populations and individual strains.
- Analysis of mutation emergence and correlation with resistance levels.
Main Results:
- Initial passages showed low-level resistance with diverse mutations and increased survival.
- Mutations in oprD and subsequently mexR genes were identified in resistant strains.
- High-level meropenem resistance and collateral resistance to ciprofloxacin were observed.
Conclusions:
- P. aeruginosa persister cells evolve resistance through sequential genetic mutations under antibiotic pressure.
- The oprD and mexR genes play critical roles in the development of high-level meropenem resistance.
- This study elucidates the dynamic interplay between persister cells and resistance evolution in P. aeruginosa.
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