Scientists have discovered a new method to produce the complex antibiotics urgently required to combat antimicrobial resistance, treat neglected diseases and tackle future pandemics.
Researchers from the University of Manchester have discovered a new way of manipulating key assembly line enzymes in bacteria which they say could pave the way for a new generation of antibiotic treatments.
CRISPR-Cas9 gene editing can be used to create new nonribosomal peptide synthetase (NRPS) enzymes that deliver clinically important antibiotics.
NRPS enzymes are prolific producers of natural antibiotics such as penicillin. However, up until now, manipulating these complex enzymes to produce new and more effective antibiotics has been a major challenge.
The Manchester team says the gene-editing process could be used to produce improved antibiotics and possibly lead to the development of new treatments helping in the fight against drug-resistant pathogens and illnesses in the future.
Jason Micklefield, professor of chemical biology at the Manchester Institute of Biotechnology (MIB), UK, said: “The emergence of antibiotic-resistant pathogens is one of the biggest threats we face today.
“The gene-editing approach we developed is a very efficient and rapid way to engineer complex assembly line enzymes that can produce new antibiotic structures with potentially improved properties.
“We are now able to use gene editing to introduce targeted changes to complex NRPS enzymes, enabling alternative amino acids precursors to be incorporated into the peptide structures.
“We are optimistic that our new approach could lead to new ways of making improved antibiotics which are urgently needed to combat emerging drug-resistant pathogens.”
The UK government suggest antimicrobial resistance (AMR) infections are estimated to cause 700,000 deaths each year globally and are predicted to rise to 10m, costing the global economy $100 trillion, by 2050.
AMR also threatens many of the UN’s Sustainable Development Goals (SDGs), with an extra 28 million people that could be forced into extreme poverty by 2050 unless AMR is contained.
Microorganisms in our environment, such as soil-dwelling bacteria, have evolved nonribosomal peptide synthetase enzymes (NRPS) that assemble building blocks called amino acids into peptide products which often have very potent antibiotic activity.
Many of the most therapeutically important antibiotics, used in the clinic today, are derived from these NRPS enzymes (e.g. penicillin, vancomycin and daptomycin).
Unfortunately, deadly pathogens are emerging which are resistant to all of these existing antibiotic drugs. One solution could be to create new antibiotics with improved properties that can evade the resistance mechanisms of the pathogens.
However, the nonribosomal peptide antibiotics are very complex structures that are difficult and expensive to produce by normal chemical methods.
To address this, the Manchester team use gene editing to engineer the NRPS enzymes, swapping domains that recognise different amino acid building blocks, leading to new assembly lines that can deliver new peptide products.
Professor Colin Garner, chief executive of the charity Antibiotic Research UK said the new method could be used to alter 40 per cent of the antibiotics that are in use today.
“Professor Jason Micklefield and his co-workers at the University of Manchester have published a novel targeted way of producing natural product antibiotics.
“Using highly specific gene-editing techniques in Streptomyces they targeted the genes responsible for the production of the antibiotic enduracidin.
“Enduracidin is one of the largest natural product nonribosomal peptide antibiotics in nature (molecular weight = 2405) and to modify the molecule chemically would be extremely challenging.
“The authors used the gene-editing technique CRISPR Cas9 to introduce highly specific changes in the enduracidin target genes resulting in slightly modified analogues.
“The authors are to be congratulated on this original piece of work.
“The gene-targeting methods Professor Micklefield and his colleagues used could have general application in altering other natural product antibiotics (approximately 40 per cent of antibiotics in use today are natural products) offering new avenues of research and treatment.
“Of course, like many early-stage projects, there is a long way to go between these lab-based studies and new and effective antibiotics ready for clinical deployment.
