Researchers from the Massachusetts Institute of Technology (MIT) have created a water-soluble version of a bacterial enzyme to be used in drug screens to help develop new antibiotics.
Published in Nature Communications and funded by the National Natural Science Foundation of China, the study focuses on a bacterial enzyme called histidine kinase, a promising target for new classes of antibiotics.
Most antibiotics work by damaging bacterial cell walls or by disrupting the synthesis of ribosomes, the cell organelles that manufacture proteins. However, none of them target histidine kinase, a crucial bacterial protein that regulates processes such as antibiotic resistance and cell-to-cell communication.
Previously, as the enzyme is a hydrophobic protein, which plays a key role in keeping a protein stable and biologically active, the protein loses its structure once removed from its normal location in the cell membrane, making it difficult to develop drugs that target it.
Performing four different functions, including phosphorylation, which adds a phosphate group to activate other proteins, and dephosphorylation, which removes phosphates, histidine kinase tends to not affect human cells as they act on amino acids as opposed to histidine.
“This protein is a good target because it’s unique to bacteria and humans don’t have it,” explained Shuguang Zhang, principal research scientist, MIT Media Lab.
Using a QTY code, which stands for the letters that represent the hydrophilic amino acids that become incorporated into the proteins, researchers worked to replace four specific hydrophobic amino acids with three hydrophilic ones and discovered that the water-soluble version of the enzyme retained its natural functions.
Using an artificial intelligence programme called AlphaFold, researchers generated a structure using the new protein and molecular dynamics simulations. They found that the protein forms stabilising hydrogen bonds with water, helping to maintain its structure.
Offering the potential to create new drugs that disrupt these functions could represent a new class of antibiotics, which are urgently needed to tackle the growing threat of antibiotic resistance, which is responsible for more than one million global deaths every year.
Researchers now plan to test this approach on methane monooxygenase, an enzyme found in bacteria that converts methane into methanol to help remove methane from the atmosphere.