# Engineered romidepsin biosynthetic pathways in Escherichia coli Nissle 1917 improve the efficacy of bacteria-mediated cancer therapy

## TL;DR

Scientists engineered a probiotic bacteria to produce an anticancer drug inside tumors, improving treatment effectiveness and reducing side effects.

## Contribution

The study introduces a novel method of using engineered bacteria to biosynthesize and deliver romidepsin directly to tumors.

## Key findings

- Engineered EcN strains produced romidepsin with a maximum in vitro yield of 1.5 mg/L.
- Recombinant strains outperformed wild-type EcN in tumor models and reduced cardiotoxicity and mortality.
- Intratumoral FK228 production combined with EcN's inflammatory response improved treatment outcomes.

## Abstract

The probiotic strain Escherichia coli Nissle 1917 (EcN), a potential member of tumor-targeting bacteria, shows great promise for cancer treatment. By leveraging engineered EcN, we can design a bacteria-assisted, tumor-targeted therapy for the biosynthesis and targeted delivery of small-molecule anticancer agents. In this study, we aimed to use EcN as a base for synthesizing Romidepsin (FK228), an FDA-approved drug originally made by Chromobacterium violaceum No. 96. Through gene cluster reconstruction, promoter optimization, and genome modification, we created FK228-producing strains to boost anticancer efficacy. The engineered strain achieved a maximum in vitro yield of 1.5 mg/L. In 4T1 tumor-bearing BALB/c mouse xenograft models, six recombinant strains outperformed the wild-type EcN. Proteome showed that inflammatory response induced by EcN combined with intratumoral FK228 production improved treatment results. Also, targeted synthesis reduced FK228's cardiotoxicity and mortality. Engineered EcN enables drug biosynthesis and precise delivery, offering powerful anticancer activity.

Bacteria-mediated cancer therapy exploits the ability of bacterial strains to specifically colonize tumors and deliver therapeutic molecules. This study engineers Escherichia coli Nissle 1917 strains to biosynthesize and deliver the anticancer drug romidepsin, achieving improved intratumoral efficacy and reduced systemic toxicity in tumor models.