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Published on: March 4, 2020
Intracellular Zn²⁺ dynamics regulate cefiderocol resistance in Klebsiella pneumoniae
Liang Wang1, Jie Zhu2, Jingnan Lv2
1Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China; MOE Key Laboratory of Geriatric Diseases and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Aims:
The worldwide spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) has posted a global threat. Treatment options for CRKP are limited, especially for strains producing New Delhi metallo-β-lactamase (NDM). The emergence of the siderophore antibiotic cefiderocol has brought hope; however, recent clinical and research data show that NDM-producing K. pneumoniae have a high rate of resistance to cefiderocol, and the reason remains unclear.
Methods:
This study focused on the dynamic changes in K.pneumoniae under host nutritional immunity and cefiderocol stress. It identified one of the main reasons for the strong cefiderocol resistance in NDM-producing strains. Further studies found that the JNMCOFLA_01041 gene plays an important role in this process and is crucial for cefiderocol resistance and virulence in K.pneumoniae.
Results:
Under host nutritional immunity and cefiderocol stress, K.pneumoniae is exposed to increasing oxidative stress. This oxidative stress results in a dynamic pattern of rapid increases in intracellular Zn²⁺ concentrations. This autonomous changes in Zn²⁺ levels in response to cefiderocol challenge can rapidly increase NDM enzyme activity and enhance the MIC, which may be one of the main reasons for the high cefiderocol minimal inhibit concentration (MIC) in NDM-producing strains. Further study identified a key gene, JNMCOFLA_01041, for Zn²⁺ and hemin absorption in K. pneumoniae. The Zn²⁺ acquisition function plays an important role in oxidative stress resistance, NDM activity, metabolism, and even pathogenicity.
Conclusions:
Taken together, our research highlights the impact of dynamic changes in bacterial metal ion concentrations on bacterial survival and drug resistance under complex host conditions. It emphasizes that, while using antimicrobial drugs, monitoring and regulating changes in the bacterial internal environment under pathological conditions is crucial for maximizing anti-infective efficacy. Furthermore, JNMCOFLA_01041 could be a target of novel drug and vaccine development.
Insights
Carbapenem-resistant Klebsiella pneumoniae (CRKP) exhibits high cefiderocol resistance due to increased intracellular zinc levels, which boost New Delhi metallo-β-lactamase (NDM) activity. The gene JNMCOFLA_01041 is crucial for this zinc uptake, resistance, and virulence.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Resistance
Background:
- Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant global health threat.
- Limited treatment options exist for CRKP, particularly strains producing New Delhi metallo-β-lactamase (NDM).
- Cefiderocol offers a potential treatment, but high resistance rates in NDM-producing strains are a growing concern.
Purpose of the Study:
- To investigate the mechanisms behind high cefiderocol resistance in NDM-producing K. pneumoniae.
- To identify key factors contributing to bacterial survival and drug resistance under host-imposed stress.
- To explore potential therapeutic targets for combating CRKP infections.
Main Methods:
- Dynamic analysis of K. pneumoniae responses to host nutritional immunity and cefiderocol stress.
- Investigation of intracellular zinc (Zn²⁺) concentration changes.
- Identification and functional characterization of the JNMCOFLA_01041 gene.
Main Results:
- Host nutritional immunity and cefiderocol stress induce oxidative stress in K. pneumoniae, leading to increased intracellular Zn²⁺.
- Elevated intracellular Zn²⁺ enhances NDM enzyme activity, increasing cefiderocol's minimal inhibitory concentration (MIC).
- The JNMCOFLA_01041 gene was identified as critical for Zn²⁺ and hemin uptake, impacting oxidative stress resistance, NDM activity, metabolism, and virulence.
Conclusions:
- Dynamic changes in bacterial metal ion concentrations significantly influence survival and drug resistance.
- Monitoring and regulating the bacterial internal environment during treatment is vital for antimicrobial efficacy.
- The JNMCOFLA_01041 gene presents a potential target for novel antimicrobial drugs and vaccines against CRKP.
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