CRISPR Gene-Drive System Defeats Antibiotic Resistance: UC San Diego Breakthrough

What Is the New CRISPR System and How Does It Work?

The pPro-MobV system, developed by Professors Ethan Bier and Justin Meyer of UC San Diego's School of Biological Sciences, represents a significant advance in the fight against antimicrobial resistance. Unlike traditional antibiotics that kill susceptible bacteria while leaving resistant strains to proliferate, this CRISPR-based approach actively removes resistance genes from bacterial populations — essentially re-sensitizing them to existing antibiotics.

The system works by introducing a genetic cassette containing CRISPR components into a bacterial cell. Once inside, the CRISPR machinery targets and disables specific antibiotic resistance genes. The key innovation of pPro-MobV is its ability to spread this genetic "fix" from cell to cell through conjugal transfer — a natural process by which bacteria exchange genetic material through direct contact. This means a single treated bacterial cell can propagate the resistance-disabling CRISPR system throughout an entire bacterial community, including into neighboring cells that have never been directly treated.

Crucially, the system has demonstrated effectiveness even within biofilms — dense, protective communities of bacteria that are notoriously difficult to penetrate with conventional antibiotics. Biofilms are responsible for many persistent infections, including those associated with medical devices, chronic wounds, and cystic fibrosis lung disease. The ability of pPro-MobV to infiltrate and modify bacteria within biofilms represents a potentially transformative advance in treating these recalcitrant infections.

Why Is Antibiotic Resistance Such an Urgent Threat?

Antimicrobial resistance (AMR) is recognized by the World Health Organization as one of the top ten global public health threats. A comprehensive analysis published in The Lancet estimated that in 2019, bacterial AMR was directly responsible for 1.27 million deaths globally and associated with an additional 4.95 million deaths — making it a leading cause of death worldwide. The six leading pathogens for AMR-associated deaths were Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa.

The crisis is driven by multiple factors: overprescription of antibiotics in healthcare settings, widespread use of antibiotics in livestock agriculture, insufficient infection prevention and control measures, and a declining pipeline of new antibiotic drugs. Pharmaceutical companies have largely retreated from antibiotic development due to unfavorable economics — antibiotics are taken for short courses and are actively conserved, making them less profitable than drugs for chronic conditions.

The O'Neill Commission, commissioned by the UK government, projected that without significant intervention, AMR could cause 10 million deaths annually by 2050, surpassing cancer as a cause of death and costing the global economy up to $100 trillion in lost output. In the United States alone, the CDC estimates that antibiotic-resistant infections affect more than 2.8 million people per year, resulting in over 35,000 deaths. Common infections that were once easily treatable — urinary tract infections, pneumonia, wound infections — are becoming increasingly difficult to manage with existing antibiotics.

What Are the Next Steps for This Technology?

The foundation for pPro-MobV was laid in 2019, when Professor Bier's lab partnered with Professor Victor Nizet's team at the UC San Diego School of Medicine to design the original Pro-Active Genetics (Pro-AG) system. That first-generation system proved the concept of using CRISPR to disable resistance genes, but required direct delivery to each bacterial cell. The conjugal transfer mechanism in pPro-MobV overcomes this critical limitation, enabling the system to propagate autonomously through bacterial communities.

Future development will focus on several key areas. First, the team aims to expand the system to simultaneously target multiple resistance genes, addressing the reality that many clinical pathogens carry resistance to several antibiotic classes. Second, extensive safety testing is needed to ensure that the CRISPR system does not inadvertently affect beneficial bacteria in the human microbiome or spread beyond the intended target population. Third, the researchers will need to demonstrate efficacy in animal models of infection before any consideration of clinical trials in humans.

The broader scientific community has also highlighted the need for regulatory frameworks to govern gene-drive technologies in bacteria, given their self-propagating nature. While the pPro-MobV system is designed to target specific resistance genes and should not affect bacteria lacking those genes, the unprecedented nature of releasing self-spreading genetic modifications into microbial ecosystems warrants careful oversight. Regulatory agencies including the FDA and EPA would need to evaluate the technology under novel assessment frameworks.