Antibiotic sensor directly binds drug in resistant bacteria
Vancomycin-resistant enterococci bacteria, or VRE, cause serious hospital-acquired infections, prompting scientists to search for new ways to target these hard-to-treat pathogens. VRE detect vancomycin through a transmembrane histidine kinase, called VanS, which phosphorylates the transcription factor VanR. Once phosphorylated, VanR triggers the production of enzymes that shield the bacterial cell wall from vancomycin’s effects. Ten genetic variants of this system exist, and disrupting it could restore vancomycin’s effectiveness. However, scientists do not understand how VanS senses vancomycin. Lina Maciunas, Photis Rotsides and a team at Drexel University College of Medicine tackled this question in their recent Journal of Biological Chemistry article.
The team developed an assay to study type-B VanS in nanodiscs, which mimic the cell membrane environment for purified membrane proteins. VanS performs three functions: autophosphorylation, transferring the phosphate group to VanR and dephosphorylating VanR. Testing these functions with vancomycin, the authors found increased autophosphorylation and slightly decreased dephosphorylation, consistent with the antibiotic activating the resistance system.
They then used a modified vancomycin photoaffinity probe and detected direct binding of the VanS sensor domain in the nanodisc, as assessed by mass spectrometry. Isothermal titration calorimetry confirmed that this interaction is specific for vancomycin since VanS did not bind a similar antibiotic.
Future work will explore how other VanS variants interact with vancomycin. Detailed insight into this interaction could guide inhibitor design to block antibiotic resistance in severe infections.
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