A bacterial enzyme called histidine kinase has long been recognized as a promising target for new antibiotics. However, its hydrophobic nature, meaning it repels water, has made it challenging to study and develop drugs that target it. This is because histidine kinase loses its structure when removed from its natural environment within the cell membrane. Now, a team of researchers led by MIT has found a way to make this enzyme water-soluble while preserving its natural functions.
The researchers achieved this by substituting four specific hydrophobic amino acids with three hydrophilic ones, effectively making the enzyme “water-loving.” Despite this significant alteration, the water-soluble version of histidine kinase retained its natural functions. This breakthrough is particularly significant because no existing antibiotics currently target histidine kinase. Drugs that successfully disrupt its functions could represent a new class of antibiotics, which are urgently needed to address the growing threat of antibiotic resistance.
Each year, more than 1 million people die from antibiotic-resistant infections,
says Shuguang Zhang, a principal research scientist in the MIT Media Lab and one of the senior authors of the new study. “This protein is a good target because it’s unique to bacteria and humans don’t have it.”
This innovative approach builds on a technique developed by Zhang and his colleagues in 2018 called the QTY code. This method involves replacing hydrophobic amino acids with hydrophilic ones, represented by the letters Q, T, and Y. Previously, the QTY code had been successfully used to create water-soluble versions of other hydrophobic proteins, including antibodies and transporters.
In this new study, published in Nature Communications, the team focused on histidine kinase due to its potential as an antibiotic target. Histidine kinase plays a crucial role in bacterial processes such as antibiotic resistance and cell-to-cell communication. Importantly, drugs that block histidine kinase are unlikely to affect human cells because human kinases act on different amino acids.
After successfully converting histidine kinase into a water-soluble form using the QTY code, the researchers confirmed that the protein retained all four of its natural functions. This finding opens the door to using this modified protein in high-throughput screens to rapidly identify potential drug compounds that can interfere with these functions.
The research team also used AlphaFold, an AI program for predicting protein structures, to generate a structural model of the water-soluble histidine kinase. Their analysis revealed that the protein forms stabilizing hydrogen bonds with water, which helps it maintain its structure.
This breakthrough has far-reaching implications beyond antibiotic development. Zhang plans to apply the QTY code to methane monooxygenase, an enzyme found in bacteria that can convert methane into methanol. A water-soluble version of this enzyme could be used to remove methane, a potent greenhouse gas, from the atmosphere.
William DeGrado, a professor of pharmaceutical chemistry at the University of California at San Francisco, who was not involved in the study, commented on the significance of the research: “It is a great advance to be able to make functionally relevant, water-solubilized proteins. An important question is how signals are transmitted across membranes, and this work provides a new way to approach that question.”
The research was funded, in part, by the National Natural Science Foundation of China.
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