Precision, Gene-Edited Antimicrobial Targets Difficult-to-Treat E. Coli

An oral, next-generation antimicrobial created using CRISPR-Cas gene editing could one day reduce the severity of a serious, food-borne infections that are generally untreatable with antibiotics.

The preclinical findings offer a potential new weapon in the armamentarium against Shiga toxin-producing Escherichia coli (STEC), a bacterium that causes nearly three million acute illnesses worldwide, mostly in children each year.

The precision gene therapy, called EB003, was able to significantly reduce the disease severity in an animal model of STEC infection.

“Although challenges such as dosing, resistance emergence, and delivery optimization remain, our findings provide a compelling foundation for the further development of EB003 and other CRISPR-based therapeutics,” reported Matthieu Galtier, PhD, of the Pasteur Institute in Paris, and co-workers in in Science Translational Medicine.

STEC is a notable public health threat, potentially causing bloody diarrhea that can progress to hemolytic uremic syndrome (HUS), a life-threatening condition with long-term implications.

Many antibiotics can stimulate the production of Shiga toxin, making infections worse and increasing the risk of HUS. They are therefore not generally recommended for infections and patients are typically only treated symptomatically.

Noting the need for strategies to eradicate STEC strains while preventing toxin release, the researchers examined the value of deploying phages—a type of virus that selectively infects and kills bacteria.

Phage-based products are already used to decontaminate food products but, as natural phages do not directly inhibit toxin production, the team investigated whether genetic engineering offered promising solution.

Galtier and colleagues engineered a delivery vector that recognized most clinical isolates from O157:H7 E. coli strains that are commonly associated with human disease, while ensuring a direct shutdown of toxin production.

Previously, the investigators had successfully used a λ phage-derived particle with engineered receptor binding proteins (RBPs) to deliver a base editor to E. coli colonizing the mouse gut.

Building on this λ-based platform, they developed EB003, a rationally engineered antimicrobial that delivers a nonreplicative CRISPR-Cas12 system programmed to target more than 99% of gene variants for stx toxins in E. coli O157 clinical isolates.

The team demonstrated that their nonreplicative CRISPR-Cas antimicrobial was efficient targeting of most clinically relevant O157 E. coli strains in vitro.

It led to a reduction of bacterial load in a mouse gut colonization model, as well as the mitigation of symptoms in an infant rabbit disease model, including reduced toxin production.

“A key advantage of EB003 over conventional antibiotics is its ability to eliminate O157 STEC without inducing Stx release, a major limitation of current treatments such as fluoroquinolones,” they reported.

“This could translate into a safer therapeutic option, reducing the risk of HUS in patients with a STEC infection.”

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