At the forefront of antibiotic research, a team from the Massachusetts Institute of Technology has made a significant advancement by creating a water-soluble variant of histidine kinase, a bacterial enzyme that holds promise as a target for new antibiotic classes. This innovative approach aims to address the pressing issue of antibiotic resistance, which claims over one million lives annually due to infections that conventional antibiotics can no longer treat effectively.
Histidine kinase is crucial for various bacterial functions, including antibiotic resistance and cell communication. However, its hydrophobic nature makes it challenging to study and target with drugs. The researchers tackled this problem by substituting four hydrophobic amino acids in the enzyme with three hydrophilic ones, successfully maintaining its natural functions. This breakthrough could pave the way for high-throughput drug screening to identify compounds that disrupt histidine kinase activity, potentially leading to new antibiotics.
The research team, led by Mengke Li from Shanghai Jiao Tong University, alongside senior authors Shuguang Zhang from MIT and Ping Xu, also from Shanghai Jiao Tong University, published their findings in Nature Communications. Their work highlights the significance of histidine kinase as a unique target for antibiotic development, as it is not present in human cells, reducing the risk of adverse effects when targeting this enzyme.
To facilitate the creation of water-soluble proteins, the researchers employed a technique known as the QTY code, which was developed by Zhang in 2018. This method has previously been applied to various hydrophobic proteins, including antibodies and transporters, and now extends to enzymes like histidine kinase. By maintaining the structural integrity of the enzyme in water, the team can conduct rapid screenings for potential antibiotic candidates that can inhibit its functions.
In their experiments, the researchers confirmed that the water-soluble histidine kinase retained all four of its critical enzymatic functions, including phosphorylation and dephosphorylation. This capability is essential for evaluating how different drug compounds interact with the enzyme, providing a robust platform for discovering new antibiotics that could combat bacterial infections.
The implications of this research extend beyond antibiotics. Zhang plans to explore the QTY code's application on other enzymes, such as methane monooxygenase, which could help mitigate climate change by converting methane into methanol. This versatility suggests that the QTY technique could revolutionize how scientists study and manipulate membrane proteins, ultimately leading to advancements in various fields, including pharmaceuticals and environmental science.
As the global fight against antibiotic resistance intensifies, this MIT-led study represents a beacon of hope. By unlocking new avenues for drug discovery through innovative protein engineering, researchers are poised to develop effective treatments that could save countless lives in the future.
