This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Tuberculosis, or TB, is a contagious bacterial infection that primarily affects the lungs. While curative treatments exist, more than 80% of cases occur in low- and middle-income nations, where drug-resistant strains are on the rise and the cost of medications is a burden.
A new class of antibiotics has shown promise against multidrug- and extensively drug-resistant TB, but its manufacturing cost is a barrier to access in poorer countries that need the treatments most. Now, researchers working with Nobel laureate Frances Arnold, Caltech's Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry, have developed a method that could lower those production costs and increase access to better treatments. "In our lab, we use enzymes—nature's catalytic machinery—to make valuable molecules in a more efficient and sustainable way," says Ziqi Li, a postdoctoral scholar research associate in the Arnold group.
"We wanted to find a more accessible route to making effective antibiotics against TB." Li is lead author of a paper published Sept. 23 in Nature that describes the team's findings. The researchers targeted a type of organic compound called 5-(S)-aminomethyl oxazolidinone, which has many pharmaceutical applications. Those applications include the synthesis of a new group of antibiotics that can target bacterial cell growth, making them promising candidates against antibiotic resistance.
Many drug molecules can exist in two mirror-image forms, much like a left and a right hand. Both forms contain the same atoms, but at one key point in the molecule, called a stereogenic center, those atoms are arranged differently in three-dimensional space. That arrangement controls the molecule's overall shape, which determines how it interacts with proteins and other biomolecules in the body.
For oxazolidinone antibiotics, only one of the two forms, known as the (S) form, kills bacteria. Oxazolidinones are often made as a mixture of the two mirror-image forms. Because only the (S) form is effective against TB, half of each batch can't be used and goes to waste.
To increase yields and potentially lower costs, Li and the team set out to build the stereogenic center from scratch using enzymes, producing only the (S) form. "We have more than 5,000 enzymes in our freezer, so we went digging into those libraries, screened a few hundred, and found one that gave us a starting point," Li says. "It wasn't necessarily a very good starting point, but we iteratively improved this enzyme to ultimately get to a final point where it's high yield and high selectivity." The process involved using directed evolution, a bioengineering method that earned Arnold the Nobel Prize in Chemistry in 2018.
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