Evolution is an incredible process, allowing life to adapt to changes in its environment. In the 1990s, the lab of Frances Arnold showed how we can turn this process to our advantage by manipulating microbes into evolving in a certain way, which could lead to new drugs and other breakthroughs. The discovery earned Arnold the 2018 Nobel Prize in Chemistry, and now her team is using the technique to develop new antibiotics.
The team is tackling a particularly challenging aspect of creating new antibiotics – making a type of molecule structure known as a beta-lactam ring. These are essentially rings of atoms that can mess with a bacterium's ability to build the outer wall of its cell, effectively killing it, and they lie at the heart of many common antibiotics, such as penicillin.
But beta-lactam rings can be tricky to make. They start off as long chains of molecules that are then folded back over themselves to form a loop. Normally, chemists would have to add extra guide molecules to tell them where to fold, and then these have to be removed later, which just adds more steps to the process and more opportunities for errors to emerge.
So the researchers set out to streamline the process, offloading the hard work to enzymes. The team, working out of Caltech, used the directed evolution technique to guide enzymes to evolve in a particular way. Once they have them doing what they want, they can transfer the enzyme's genetic code into bacteria, which will produce those enzymes.
In this case, the team evolved an enzyme called cytochrome P450 so that it could build beta-lactams. They also made other enzymes that could build other types of these structures, including gamma-lactams and delta-lactams. The difference between those is how many atoms are in each – beta-lactams are made with three carbon atoms and one nitrogen atom, while gamma-lactams boost that to four carbon atoms and delta-lactams go one further.
"We're developing new enzymes with activity that cannot be found in nature," says Inha Cho, co-author of the study. "Lactams can be found in many different drugs, but especially in antibiotics, and we're always needing new ones."
The team says these enzymes are the most efficient ones they've ever made, with each one capable of producing up to a million beta-lactam molecules. These molecules are apparently ready for industrial use – which is good news, considering just how fast bacteria are developing resistance to our best antibiotics.
The research was published in the journal Science.
Source: Caltech