PmrA Mutations in Drug-Resistant Acinetobacter baumannii Affect Sensor Kinase-Response Regulator Interaction and...

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Multidrug resistance in Acinetobacter baumannii is a critical public health concern.
• Polymyxins are last-line antibiotics, but resistance is emerging in A. baumannii.
• Polymyxin resistance is linked to the PmrAB two-component system, involving PmrA-mediated lipooligosaccharide modification.

Purpose of the Study:

• To investigate the functional impact of specific PmrA mutations found in resistant A. baumannii isolates.
• To understand how these mutations affect PmrA's interaction with PmrB and its phosphorylation status.

Main Methods:

• Characterization of five PmrA mutations (D10N, M12I, I13M, G54E, S119T).
• Assessed changes in PmrA DNA-binding affinity, dimerization, phosphorylation, and structure.
• Evaluated the impact on PmrA's interaction with the sensor kinase PmrB.

Main Results:

• The studied PmrA mutations impair the protein's ability to accept a phosphoryl group from PmrB.
• This impaired phosphorylation may result from disrupted PmrB-PmrA interaction or perturbation of PmrA's active site.
• Slowed phosphorylation can potentially enhance PmrA-mediated gene transcription.

Conclusions:

• PmrA mutations conferring polymyxin resistance in A. baumannii affect its phosphorylation mechanism.
• Understanding these molecular mechanisms is crucial for combating antibiotic resistance.
• These findings provide insights into PmrA-regulated resistance pathways in Acinetobacter baumannii.