Get into the groove: Tackling antimicrobial resistance with synthetic genes

Posted on April 1, 2015   by Nancy Mendoza

“Biotechnology is set to be the next industrial revolution, and I didn’t want to miss it!” That’s what Chemical Engineer, Emilio Cortes-Sanchez said when asked why he turned to microbiology in his search for new antimicrobial treatments. Emilio’s work was presented earlier this week at the Society’s Annual Conference.

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Antimicrobial resistance (AMR) is a growing problem, worldwide. According to a recent review commissioned by the UK government, AMR could cost millions of lives in the coming years if we don’t take action.

Around 60-70% of all known antibiotics are produced by a family of bacteria called actinomycetes. Some of these molecules are too toxic to use in humans but are providing the inspiration for chemists and microbiologists working in collaboration at Strathclyde University, who are searching for new antimicrobial therapies.

Different strains of Streptomyces bacteria, all members of the actinomycete family, make two of these toxic antibiotics: distamycin and congocidin. These molecules bind directly to the DNA inside a bacterial cell to disrupt the most basic of biological processes and kill the cell outright. They are, however, very specific about where they bind to DNA – they lock on to certain sequences within a part of the double helix structure called the minor groove.

“The source of their specificity is in the way distamycin and congocidine are put together through the normal process of synthesising peptides – small protein molecules – inside bacterial cells. So, if we want to change them, we have to change how they are built,” Emilio explained.

Imagine a string of beads of different colours, shapes and sizes being strung together on a necklace – this is, in essence, the way that peptides are built from single amino acids. To change the character of the necklace you can change the length of the string or you can change the order of the beads, and this is exactly what Emilio has been doing.

“We noticed that the genes involved in making distamycin and congocidine were quite similar but the two peptides actually behave quite differently inside the cell. We decided to investigate what might happen if we made some changes.”

First of all, the team wanted to find out the minimum set of genes required to assemble the two antibiotics. They started by putting the distamycin genes in a congocidine-producing strain and vice versa. What they ended up with in each case was a hybrid molecule comprised of parts of both antibiotics. This raises the possibility of designing synthetic genes capable of making a precise hybrid that might be a better antibiotic than either of the originals.

The team has also looked at how they could use the original gene sequences of distamycin and congocidin but chemically alter the resulting antibiotics by changing elements of the amino acids that make them – a round bead on the necklace could be filed down to make it square, for example.

There is a lot of work still to be done, and Streptomyces species can be quite difficult to work with, but early results are quite promising. “They are very complex bacteria,” Emilio said, “which is a good thing, in that there are a lot of opportunities to introduce changes, but they are difficult to grow in the lab and can pick up genetic changes quite randomly and without warning!”

This engineering approach to biological systems is part of the rapidly growing field of synthetic biology.

Synthetic biology forms a core part of the field of industrial biotechnology and seeks to develop products, tools, and technologies based on new or redesigned biological parts, devices and systems. Applications include drug development, biofuels, alternatives to oil-derived materials and sustainable food production.

In synthetic biology, micro-organisms are able to synthesis complex molecules far more easily and efficiently than organic chemists are able. However, they may not do so naturally, requiring a degree of genetic engineering. This is not a new idea – human insulin has been synthesised in this way, for the treatment of type-1 diabetes, since the early 1980s.

“We are hopeful that our approach will lead to much-needed new antibiotics,” Emilio concluded.

Image: Pörrö on Flickr under CC BY-NC-SA 2.0