King's College London

A discovery made by scientists in the Department of Chemistry could speed up efforts to produce new antibiotics in the fight against antimicrobial resistance.

In a paper published in the Journal of the American Chemical Society, King's chemists share a new, rapid method for making cyclic peptides – an important class of antibiotic molecules. The approach takes minutes rather than the hours or days it normally takes, helping overcome a major challenge in antibiotic development.

With antimicrobial resistance (AMR) a major and growing threat to public health around the world, new antibiotics are urgently required. Yet modifying or designing antibiotics to evade resistance is challenging due to the complexity of their molecular structure. Some are formed of cyclic peptides – strings of amino acids joined together in a circle – which are very difficult to replicate in the lab.

Most antibiotics are produced by fermenting fungi and bacteria, exploiting the creation of complex and naturally occurring molecules, used by microbes to compete against other strains of bacteria. However, due to overreliance on the same antibiotic products over decades, the bacteria they treat is becoming more and more resistant, signalling a major global challenge.

Lead author Dr Sarah Barry said, “The global rise in antimicrobial resistant infections is putting the huge gains in modern medicine over the last century at risk. Everything from a cut in your finger to major surgery or cancer treatment requires the use of antibiotics. But when bacteria and viruses evolve to evade these medicines, these life-saving drugs lose their effectiveness.

“We urgently need to invest in antibiotic development – and we hope that breakthroughs like our new method at King’s can inspire renewed efforts towards this goal.”

To The scientists based their study on a naturally produced cyclic peptide which has promising activity against Mycobacterium tuberculosis, the bacteria that causes of tuberculosis (TB). Someone dies from TB every 20 seconds, making it the world’s most infectious disease. But it is increasingly becoming more resistant to the antibiotics used to treat it.

Dr Barry said, “Whilst it’s very easy to make linear peptides - long strings of amino acids, artificially cyclising them using chemical methods is very challenging.”

The team found that when using the encoded sequence of amino acids from the natural peptide to make their synthetic peptides, it enabled their peptides to close into cycles incredibly quickly. They believe this simple approach can be used to make modified versions of the molecules used in antimicrobials, which can be used to develop new antibiotics.

Dr Yaoyu Ding, Research Assistant whose PhD was based on the project, said, “We have made a key part of the chemistry involved in making these molecules far easier and quicker. We hope that this chemistry will enable researchers to make libraries of derivates to enable screening for new antimicrobials."

While their primary interest was in antimicrobials, the scientists have also successfully tested this process on a range of other peptides, opening the way for applying this approach to cyclic peptide discovery for a range of therapeutic needs including anti-cancer agents.