3D Enzyme Imaging Could Help Scientists Create New Antibiotics 

Antibiotics are drugs that fight bacterial infections, either by killing the bacteria or impeding their reproduction. First discovered in the early 20^th century, antibiotics transformed medicine and have saved countless lives. However, an increasing number of bacteria have developed antibiotic resistance and no longer respond to treatment.

According to the US Centers for Disease Control (CDC), antibiotic resistance is now one of the world’s most pressing public health problems. Every time someone takes an antibiotic, the sensitive bacteria die, but bacteria resistant to the drug may survive. These resistant bacteria grow and multiply, resulting in bacterial strains that no longer respond to the typical antibiotic treatment.

The problem has primarily been caused by improper use of antibiotics. The United States alone spent $10.7 billion on antibiotics in 2009, but it’s estimated that more than half of antibiotic prescriptions are inappropriate, most often for patients seeking treatment for ailments caused by viruses rather than bacteria.

As a result, antibiotic resistance has become an increasingly important problem. The CDC says that every year in the United States, at least two million people become infected with drug-resistant bacteria and at least 23,000 people die as a direct result of those infections.

With such high stakes, there is a clear need for new antibiotics, and recent research from McGill University may help scientists in the quest to develop next-generation antibiotic therapeutics.

Medicine-Synthesizing Megaenzymes

The team of McGill University researchers, led by Dr. Martin Schmeing, wanted to get a better look at nonribosomal peptide synthetases (NRPSs), which are commonly referred to as megaenzymes. These enzymes, which are the second biggest proteins known to man, are essential to producing many common antibiotics, including penicillin and cyclosporin. They function within bacterial cells as miniature assembly lines, combining building blocks via chemical reactions to create new compounds. Because bacteria are constantly competing with other bacteria, many of the NRPS-created compounds are designed to kill other bacteria – which means they can be used as antibiotics.

To study these medicine-synthesizing enzymes, researchers first need to be able to see them. However, taking clear pictures of NRPSs is not easy; they have many parts and those parts are in constant motion.

Capturing 3D Images

In their recent study, published in Nature, the McGill University researchers took a series of 3D pictures of the initiation module of the NRPS that produces gramicidin, an antibiotic that is an active ingredient in Polysporin cream. They first used chemical traps to paralyze the proteins in the desired position; the enzymes could grab the chemical but because there was something slightly wrong with it, the enzymes could not continue onto the next step in the building process.

Then, the researchers used X-ray crystallography, a popular technique for determining protein structure, to capture 3D images. “This is the most complete view we’ve ever had of these enzymes in action,” said Dr. Schmeing in a McGill University press release.

The images can now be used by scientists to better understand how many antibiotics are made, and this knowledge could lead to the development of improved antibiotics.

“These 3D pictures revealed the totally remarkable way the NRPS works to synthesize its product. Parts of other NRPSs have been pictured before, but there have never been so many snapshots of the different steps of synthesis, and never pictures of NRPSs that incorporate interesting chemical modifications into the antibiotic,” added Janice Reimer, a PhD student and the first author on the paper. “These pictures reveal the exquisite way these parts repurpose and recycle their limited surfaces to interact with the rest of the enzyme. Once we understand enough, we can use modern bioengineering techniques to modify NRPSs to produce all sorts of products with designer modifications, perhaps giving a veritable treasure trove of new medicines.”

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