Scientists have developed a method to convert plastic waste into the widely used drug paracetamol through a novel integration of abiotic chemistry with microbial metabolism, according to a study.

The research team demonstrated that Escherichia coli bacteria could host a biocompatible Lossen rearrangement—a chemical reaction not naturally observed in living systems. This non-enzymatic transformation, traditionally used in synthetic organic chemistry to produce amines, was shown to occur inside living cells, catalyzed by phosphate ions present in standard bacterial growth media. Crucially, the reaction took place under physiological conditions, required no metal catalyst or enzyme, and was non-toxic to E. coli.

In this study, researchers synthesized a reactive compound designed to undergo the Lossen rearrangement from polyethylene terephthalate (PET)—a common plastic found in bottles. When this PET-derived molecule was introduced into E. coli strains deficient in para-aminobenzoic acid (PABA), a metabolite required for folic acid biosynthesis and cell growth, the bacteria resumed growth. This auxotroph rescue confirmed that the rearrangement successfully produced PABA inside the cells, enabling the bacteria to survive and grow.

Further testing revealed that the rearrangement was phosphate-catalyzed and proceeded without the aid of any engineered enzymes or protein catalysts. Instead, the bacteria served as a compatible environment for the reaction, with phosphate ions acting as the true catalyst—a novel example of integrating purely chemical reactivity into a biological system.

After demonstrating in vivo PABA synthesis, researchers engineered E. coli to metabolically convert the newly formed PABA into paracetamol (acetaminophen) through a two-step pathway. They introduced two additional genes:

• One encoding an enzyme from Agaricus bisporus that converts PABA into 4-aminophenol, and

• Another encoding a modified enzyme from Pseudomonas aeruginosa that acetylates 4-aminophenol to produce paracetamol.

By using a two-strain system to optimize expression of these enzymes, and carefully staging the biotransformation process, the team achieved up to 92% yield of paracetamol from the PET-derived substrate under optimized conditions. Both the PET-based compound and the final drug were non-toxic to the bacterial cells at concentrations relevant for fermentation.

This study marks the first in vivo demonstration of a Lossen rearrangement integrated with microbial metabolism. It presents a potential strategy for upcycling plastic waste into pharmaceutical compounds using a combination of chemical synthesis and engineered biology—something not achievable by either method alone.

The researchers suggest that this approach could offer a sustainable alternative to conventional drug synthesis, which often depends on fossil-fuel-derived feedstocks. Future work will focus on scaling the system to industrial reactors, refining the synthetic pathway, and exploring the integration of other abiotic reactions into living microbial platforms.

Full disclosures can be found in the published study.

Source: Nature Chemistry