New "Programmable" Antibiotic Targets Drug-Resistant Genes

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A fundamental drawback to antibiotics is that they indiscriminately target all of the bacteria in your body, including the good ones. So how cool would it be if we could engineer a smart antibiotic that targets specific strains of bacteria? Researchers at Rockefeller University have just taken us one major step forward in that direction.

This breakthrough is important for at least two reasons. Not only does the new programmable antibiotic selectively target undesirable microbes, it's also engineered to target those microbes that contain antibiotic-resistant genes. Importantly, it leaves the innocent microbes alone. The technique could conceivably be used against so-called "superbugs" that are adapting to modern antibiotics. Also, the approach could, for example, reduce the risk of severe infections of the colon caused by the Clostridium difficile bacterium — a bug that's associated with extended courses of harsh antibiotics.


To make it work, the researchers instructed a bacterial enzyme, called Cas9, to target a particular DNA sequence and slice it to pieces. It's a selective approach that leaves the healthy microbial community intact, thus keeping resistance in check and preventing certain types of secondary infections.

An article from The Rockefeller University Newswire explains:

The Cas9 enzyme is part of a defense system that bacteria use to protect themselves against viruses. The team co-opted this bacterial version of an immune system, known as a CRISPR (clustered regularly interspaced short palindromic repeats) system and turned it against some of the microbes. CRISPR systems contain unique genetic sequences called spacers that correspond to sequences in viruses. CRISPR-associated enzymes, including Cas9, use these spacer sequences as guides to identify and destroy viral invaders.

The researchers directed Cas9 at targets of their choosing by engineering spacer sequences to match bacterial genes and then inserting these sequences into a cell along with the gene for Cas9. The cell's own machinery then turns on the system. Depending on the location of the target in a bacterial cell, Cas9 may kill the cell or it may eradicate the target gene. In some cases, a treatment may prevent a cell from acquiring resistance, they found.

"We previously showed that if Cas9 is programmed with a target from a bacterial genome, it will kill the bacteria. Building on that work, we selected guide sequences that enabled us to selectively kill a particular strain of microbe from within a mixed population," says first author David Bikard, a former Rockefeller postdoc who is now at the Pasteur Institute in Paris.


The final set of experiments confirmed their preliminary results on living skin by using Cas9 to selectively kill kanamycin-resistant Staph infecting the shaved backs of mice.


The researchers colonized mouse skin with a mixture of bacterial cells, some resistant to the antibiotic kanamycin. The resistant cells were made to glow (left) and treated with an enzyme that targeted and destroyed most resistant cells (right). Credit: Marraffini Lab and Fischetti Lab / Nature Biotechnology

Despite the promising results, the researchers say the delivery system needs improvement. The bacteria-infected viruses that they employed only attack specific types of cells. Ideally, they'd like to develop a less discriminating method of delivery. Assuming that can be done, we may see the introduction of a completely new class of antibiotics.


Read the entire study at Nature Biotechnology: "Exploiting CRISPR-Cas nucleases to produce sequence-specific antimicrobials". Supplementary info via Rockefeller University.

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