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Reversion of Ceftazidime Resistance in Pseudomonas aeruginosa under Clinical Setting
Qi Liu1, Liwen Yin1, Xinxin Zhang1
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:
Pseudomonas aeruginosa is an important nosocomial pathogen which frequently becomes resistant to most antibiotics used in chemotherapy, resulting in treatment failure among infected individuals. Although the evolutionary trajectory and molecular mechanisms for becoming β-lactam resistant have been well established for P. aeruginosa, the molecular basis of reversion from β-lactam resistant to susceptible is largely unexplored. In this study, we investigated the molecular mechanisms by which a ceftazidime-resistant clinical strain is converted to a ceftazidime-susceptible isolate under the clinical setting. RNA sequencing and genomic DNA reference mapping were conducted to compare the transcriptional profiles and chromosomal mutations between these two isolates. Our results demonstrate that a gain-of-function mutation in ampD, via deletion of a 53 bp duplicated nucleotide sequence, is the contributory factor for the conversion. Furthermore, we show for the first time that AmpD is involved in intraspecies competitiveness in P. aeruginosa. We also found that AmpD is not responsible for phenotypic changes between R1 and S2, including growth rate, motilities, pyocyanin, rhamnolipid, and biofilm production. This finding provides novel insights into the alteration of β-lactam sensitivity in P. aeruginosa under the clinical setting.
Insights
Pseudomonas aeruginosa can revert from antibiotic resistance to susceptibility. A mutation in the ampD gene, identified through RNA sequencing, drives this reversion in clinical settings.
Area of Science:
- Microbiology
- Genetics
- Molecular Biology
Background:
- Pseudomonas aeruginosa is a significant nosocomial pathogen.
- Antibiotic resistance, particularly to beta-lactams, is a major clinical challenge.
- Mechanisms of beta-lactam resistance are known, but reversion to susceptibility is poorly understood.
Purpose of the Study:
- To investigate the molecular mechanisms behind the reversion of a ceftazidime-resistant Pseudomonas aeruginosa strain to ceftazidime susceptibility.
- To identify genetic alterations responsible for this phenotypic switch in a clinical isolate.
Main Methods:
- Comparative analysis of a ceftazidime-resistant and a ceftazidime-susceptible clinical isolate of Pseudomonas aeruginosa.
- RNA sequencing to compare transcriptional profiles.
- Genomic DNA reference mapping to identify chromosomal mutations.
Main Results:
- A gain-of-function mutation in the ampD gene, specifically a 53 bp deletion in a duplicated sequence, was identified as the cause of ceftazidime susceptibility.
- The study demonstrates AmpD's role in intraspecies competitiveness in Pseudomonas aeruginosa.
- AmpD was found not to influence phenotypic traits like growth rate, motility, or biofilm production.
Conclusions:
- A specific mutation in ampD is responsible for the reversion of Pseudomonas aeruginosa from ceftazidime resistance to susceptibility.
- This finding offers new insights into the dynamic alteration of beta-lactam sensitivity in clinical Pseudomonas aeruginosa strains.
- AmpD has a novel role in bacterial competitiveness beyond its known function in cell wall metabolism.
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