Scientists have discovered a new way to produce complex antibiotics by harnessing gene editing to reprogram pathways to future drugs urgently needed to fight antimicrobial resistance, treat neglected diseases and prevent future pandemics.
Researchers at the University of Manchester have discovered a new way to manipulate key enzymes in the assembly line in bacteria, which could pave the way for a new generation of antibiotic treatments.
New research published today in Nature Communication, describes how CRISPR-cas9 gene editing can be used to create novel non-ribosomal peptide synthetase (NRPS) enzymes that deliver clinically important antibiotics. NRPS enzymes are prolific producers of natural antibiotics such as penicillin. However, until now, the manipulation of these complex enzymes to produce new, more effective antibiotics has been a major challenge.
The problem of antimicrobial resistance
According to the UK government, it is estimated that antimicrobial resistance (AMR) infections cause 700,000 deaths worldwide each year and are expected to reach 10 million, which will cost the global economy $ 100,000 billion by 2050. The Antimicrobial resistance also threatens many UN Sustainable Development Goals (SDGs), with an additional 28 million people who could be forced into extreme poverty by 2050 if AMR is not contained.
The Manchester team say the gene-editing process could be used to produce improved antibiotics and possibly lead to the development of new treatments to help fight drug-resistant pathogens and diseases in the future. Jason Micklefield, professor of chemical biology at the Manchester Institute of Biotechnology, UK, explains: âThe emergence of antibiotic-resistant pathogens is one of the greatest threats we face today.
“The gene editing approach we have developed is a very efficient and rapid way to design complex assembly line enzymes that can produce new antibiotic structures with potentially improved properties.”
The potential of non-ribosomal peptide antibiotics
Microorganisms in our environment, such as bacteria living in the soil, have developed non-ribosomal peptide synthetase (NRPS) enzymes that assemble building blocks called amino acids into peptide products that often have very potent antibiotic activity. Many of the most important therapeutically important antibiotics in clinical use today are derived from these NRPS enzymes (eg, penicillin, vancomycin, and daptomycin).
Unfortunately, deadly pathogens are emerging that are resistant to all of these existing antibiotic drugs. One solution could be to create new antibiotics with improved properties that can escape the resistance mechanisms of pathogens. However, non-ribosomal peptide antibiotics are very complex structures which are difficult and expensive to produce by normal chemical processes. To solve this problem, the Manchester team uses gene editing to design NRPS enzymes, swapping domains that recognize different amino acid constructs, leading to new assembly chains that can provide new peptide products.
Micklefield added: âWe are now able to use gene editing to introduce targeted changes in complex NRPS enzymes, by introducing alternative amino acid precursors into peptide structures. We are optimistic that our new approach could lead to new ways to make improved antibiotics that are urgently needed. to combat emerging drug-resistant pathogens.
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