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Biosensor for Detection of Antibiotic Resistant Staphylococcus Bacteria
Published on: May 8, 2013
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Two-Component System Sensor Kinase Inhibitors Target the ATP-Lid of PmrB to Disrupt Colistin Resistance in
Alexander D Hondros1, Milah M Young2, Felicia E Jaimes1
1Department of Biochemistry & Molecular Biology, Brody School of Medicine East Carolina University, Greenville, North Carolina 27834, United States.
Biochemistry
|March 8, 2025
Summary
Researchers developed a new method to study bacterial communication systems, identifying compounds that block antibiotic resistance in Acinetobacter baumannii. This discovery offers potential new strategies against colistin resistance.
Area of Science:
- Microbiology
- Bacterial signaling pathways
- Antimicrobial resistance mechanisms
Background:
- Two-component systems regulate bacterial responses, including antimicrobial resistance.
- The PmrAB system in Acinetobacter baumannii is crucial for colistin resistance.
- Studying the membrane-bound histidine kinase PmrB has been challenging.
Purpose of the Study:
- To overcome limitations in studying the PmrAB system.
- To identify inhibitors of the PmrB histidine kinase.
- To develop strategies to combat colistin resistance.
Main Methods:
- Produced a recombinant cytosolic portion of PmrB (PmrBc) with retained functions.
- Utilized in vivo phosphorylation assays to screen PmrBc inhibitors.
- Employed mass spectrometry and limited proteolysis to determine mechanisms of action.
Main Results:
- Five compounds (IMD-0354, NDM-265, NDM-455, NDM-463, NDM-497) were identified as PmrBc inhibitors.
- These inhibitors blocked PmrB autophosphorylation and phosphotransfer.
- In vivo administration of these compounds eliminated colistin resistance.
- The compounds' binding site on the ATP-lid of PmrB was elucidated.
Conclusions:
- A functional recombinant PmrBc was successfully produced, enabling new research avenues.
- Identified PmrB inhibitors offer a promising strategy to overcome colistin resistance in Acinetobacter baumannii.
- Understanding the mechanism of action provides a basis for developing novel antibiotic adjuvant therapies.
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