CRISPR genome editing could be game changer in war against antibiotic resistance

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Genomic Tape Recorder

Health officials and clinicians are worried about a potential post-antibiotic era of medicine in which infectious disease becomes the main killer, even in developed countries. This is how things were a century ago and it’s a frightening prospect that looms on the horizon, even as medicine advances in gene therapy, bionics, and organ synthesis—all areas that potentially could extend the human lifespan by centuries. But since Alexander Fleming’s discovery of penicillin 1928, we’ve been at war against evolution. We’ve been in an arms race against bacteria. We develop new drugs that attack one type of bacterial Achilles heal or another, but then—through the sieve of selection—they develop new armor.

To change the nature of the war, humans need more than simply more of the same kind of weapon. We also need another category of weapon, something other than antibiotics. Until recently, such a prospect sounded like science fiction. But the harnessing of CRISPR genome editing in the last few years has changed everything. Using it, researchers are starting a new trend, which is to strip the enemy of its acquired armor so that the old weapons will be more effective than ever.

Conventional approaches

Antibiotic resistance has been evolving due to selective pressures resulting both from clinical use of antibiotics to treat humans against bacterial infection, and from subclinical levels of antibiotics used in livestock.

To be sure, we’ve redoubled our efforts. Researchers develop new drugs constantly. But there’s a pecking order of antimicrobial agents that in certain clinical situations can be thrown at difficult infection, leading to a last resort drug for a particular condition. With Gram-positive bacteria, for instance, when faced with multi-drug resistance, physicians traditionally have turned to vancomycin as a last resort, but vancomycin-resistant strains have been documented in human patients for more than a decade. For Gram negative strains like E. ColiPseudomonas aeruginosa, and Klebsiella pneumoniae, the last resort drug has been polymyxin E (Colistin), but two months ago the Centers for Disease Control (CDC) announced the identification of Colistin-resitant E. coli in a patient. It’s the first case on US soil and the resistance to the drug was found to be connected with a gene called mcr-1. In addition to strains of E. coli armored against our best pharmaceutical weapons, mcr-1 can transfer antibiotic resistance to other bacteria which some have warmed could herald an ‘antibiotic apocalypse‘.

Researchers are always working to develop new anti-microbial drugs, but the growing knowledge of the basis for genetic drug resistance is serving as a basis for additional strategies that potentially can become part of a multi-pronged attack.

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Attacking bacterial armor in vivo

An antibacterial tactic that researchers have been studying for decades in laboratory animals is to utilize bacteriophages (or just phage), viruses that infect bacteria. These phages can be used to deliver genetic entities called plasmids into the bacterial genome. Armed with the right the genetic payload, the phage-delivered plasmid can act as a Trojan horse and destroy the bacterium. This approach would entail delivering the bacteriophages in vivo through a patient’s bloodstream, but there’s an automatic disadvantage: non-pathogenic bacteria are killed off just as easily as pathogens, which is not the best-case scenario if the goal is to cure disease.

Role for CRISPR editing

Realizing the negatives of the in vivo approach, investigators such as MIT’s Timothy Lu, Professor of Biological and Electrical Engineering, prefer the idea of taking control of bacterial evolution in the environment, rather than inside patients. This is an area where CRISPR genome editing can come in particularly handy. ““The idea of CRISPR-based approaches is to enact sequence-specific antimicrobial activity, placing selective pressure against genes that are bad rather than conserved bacterial targets,” Lu has noted.

In a paper published in the May issue of the prestigious Proceedings of the National Academy of Sciences (PNAS), Udi Qimron and his team at Tel Aviv University, in Ramat Aviv Israel, have demonstrated feasibility of a modified form of phage therapy. The “therapy”, is not sent into the infected patient or animal model, however. Rather, a CRISPR-Cas system is released into the environment, consisting of a Cas to remove antibiotic resistance genes such as mcr-1 and an RNA sequence that locates those genes. Rather than drawing the editing system to a particular bacterial species, the system goes after the resistance genes in nature. This, in turn, should place an obstacle against bacteria that have evolved to spread by infecting and multiplying within animal hosts—pathogenic bacteria. Combined with use of the many antibiotics that we do have, humans could not only can regain their fading advantage against pathogenic bacteria, but perhaps finally pull ahead.

David Warmflash is an astrobiologist, physician and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

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