Can a biosynthetic pathway be a new route to antibiotic use?

Can a biosynthetic pathway be a new route to antibiotic use?
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Scientists have discovered a new route to antibiotic use, exploiting a chemical process and gene editing, also known as a biosynthetic pathway.

Researchers from The University of Manchester’s School of Chemistry, UK, have discovered a new chemical process, known as a biosynthetic pathway, in bacteria which could pave the way for a new generation of antibiotics being produced and manufactured. According to the researchers, the new pathway includes the enzyme, called a carboxylase, which adds CO2 to a precursor molecule producing a highly unusual antibiotic known as malonomycin. This antibiotic use also has the potential to lead to the discovery and development of other drugs.

The biosynthetic pathway and its process

Antibiotic resistance could result in an estimated 10 million deaths every year by 2050, whilst the cost to the global economy could be £66 trillion (~€74.5 trillion) in lost productivity.

Across Europe alone, an estimated 25,000 people already die each year as a result of hospital infections caused by the antibiotic resistant bacteria such as Escherichia coli (E. coli).

The research team says the biosynthetic pathway process used to produce this antibiotic could now possibly lead to the discovery and development of other drugs, helping in the fight against drug-resistant bugs and illnesses in the future.

Jason Micklefield, professor of chemical biology at the Manchester Institute of Biotechnology, UK, explains: “The rapid rise of antibiotic-resistant pathogens is one of the foremost global health concerns of modern times.

“Now, using a combination of bioinformatics, gene editing and in vitro experiments, we have discovered a highly unusual biosynthetic pathway to the antibiotic malonomycin. This could pave the way for a new kind of antibiotic production process.”

The interest in malonomycin and the potential antibiotic use

Particularly interested in its highly unusual chemical structure, the researchteam focused particularly on malonomycin. It possesses potentially useful antimicrobial activity and has already attracted industrial attention. However, despite the interest in its antibiotic use, very little was known about the biosynthetic pathway of malonomycin, until now.

CO2 was introduced into the malonomycin structure, by a carboxylase enzyme that has never been characterised in bacteria before. Malonomycin carboxylase is most similar to a carboxylase enzyme in human cells which uses vitamin K to add CO2 to proteins in our bodies, triggering essential physiological responses including blood coagulation.

Clinically important anticoagulant drugs, such as warfarin, function by blocking the human vitamin K-dependent carboxylase. Micklefield added: “We were very surprised to find an antibiotic-producing carboxylase enzyme in bacteria that was similar to the human carboxylase responsible for blood clotting.

“We are now optimistic that our findings might lead to the discovery of new antibiotics and may also provide new ways of making antibiotics which are urgently needed to combat emerging drug-resistant pathogens.”

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