Antibiotic resistance is one of the defining challenges of the 21st Century. Over 700,000 people die globally as a result of antibiotic resistant infections each year. The World Health Organization has issued a dire warning about the prospect of a “post-antibiotic era” if the spread of antibiotic resistance continues unabated. Without actions to address this crisis, the consequences are dire; an estimated 300 million people are expected to die from antibiotic resistant infections by 2050 and up to 100 trillion USD in economic output could be lost. The effects of a “post-antibiotic” era will be particularly devastating for the world’s poorest; the World Bank projects that superbugs will push 28 million people into extreme poverty by 2050, erasing many of the economic development gains made in the developing world over the past fifty years.
CRISPR-based antibiotics: A novel solution for antibiotic resistance
Despite growing urgency worldwide, the pace of drug development has not kept up with the need for innovative antibiotics. In fact, the pipeline for new antibiotics has trickled to a halt worldwide (reference Figure 1). Not a single new class of antibiotics has been discovered since 1984, and as of September 2016, only forty antibiotics were in active clinical development. Antibiotics have limited economic appeal to pharmaceutical companies due to the short duration of treatment and restricted use to maintain their effectiveness. In addition, antibiotic drug discovery is a time-intensive and laborious process to identify and validate clinical targets and screen potential compounds for efficacy and safety. Most antibiotics fail to demonstrate sufficient therapeutic efficacy and safety to be tested in clinical trials. The antibiotics in active clinical development face long odds and a low likelihood of approval; as few as one in six antibiotics that enter clinical trials in the United States will be approved. With the Research & Development (R&D) costs of bringing a drug to market reaching almost $2.6 billion USD in 2016, pharmaceutical firms have all but abandoned antibiotic R&D in favor of more lucrative therapeutic areas such as diabetes and cancer.
It is clear that the existing R&D efforts alone will not sufficiently replenish our armamentarium of antibiotics to manage the growing threat of antibiotic resistance. Although new antibiotics can provide temporary stopgaps in our race to combat the rise of drug-resistant bacteria, we will continue to lose the war against these superbugs if we cannot preserve the effectiveness of our existing stock of antibiotics.
The fundamental challenge in addressing the problem of antibiotic resistance is the ability of bacteria to mutate and evolve. Based on the principles of natural selection, the bacteria that will survive and transmit their genes to the next generation possess advantageous mutations that enable them to adapt to their environments. Bacteria with resistance genes can therefore survive in the presence of antibiotics and increase in number, resulting in an increased frequency of resistance in the overall bacterial population. These bacterial species can also acquire multiple antibiotic resistance genes through the lateral exchange of genetic material with other bacteria, becoming even more difficult to kill in the process. As a result, existing antibiotics gradually lose their effectiveness over time due the spread of resistance, resulting in the proliferation of drug-resistant superbugs.
However, the recent discovery of a gene editing tool known as Clustered Regularly Interspaced Palindromic Repeats (CRISPR) has the potential to revolutionize the treatment of bacterial infections and refortify our existing supply of antibiotics. By leveraging the power of gene editing, CRISPR offers a customized therapeutic approach that addresses the fundamental issue of genetic mutation that underlies the problem of antibiotic resistance. I propose applying this novel gene editing technology to address the growing challenge of antibiotic resistance.
CRISPR was discovered in bacteria as an innate defense mechanism against invading viruses. The technique uses an enzyme known as Cas9 that acts as a molecular scissor to cut the cell’s DNA at a target sequence (reference Figure 2). Cas9 cleaves at a target sequence specified by a guide RNA; this guide RNA is customized to match the desired DNA sequence to be edited. CRISPR can easily delete genes from an organism’s genome and can be used to add new DNA sequences that could theoretically reverse the deleterious effects of a genetic mutation.
CRISPR can be engineered to exclusively target drug-resistant bacteria and facilitate their eradication from the human body. CRISPR can functionally delete the parts of the genome that cause antibiotic resistance in pathogenic bacteria, rendering these bacterial species susceptible to existing antibiotics. This approach can diminish the need for conventional broad-spectrum antibiotics, which can non- selectively eliminate beneficial bacteria in the human gut microbiome that play a role in metabolism and immunity.
Why are CRISPR-based antibiotics disruptive? The genetic sequence targeted for deletion by the CRISPR construct can be changed to reflect the newest bacterial mutations that confer antibiotic resistance. In the face of the continued evolution of drug-resistant pathogens, this approach can enable our existing therapeutic arsenal of antibiotics to maintain its effectiveness. In addition, CRISPR is highly scalable and can be used to target multiple bacterial species and multiple antibiotic resistance genes all at once. In short, CRISPR-based antibiotics have the potential to offer a personalized, targeted therapeutic approach for antibiotic resistance, strengthen our public healthcare infrastructure, and reduce healthcare expenditures worldwide. Although this disruptive technology is in its earliest stages of development, studies have suggested that CRISPR gene editing technology may have promise in combatting Methicillin-resistant Staphylococcus aureus (MRSA), a growing cause of hospital infections. In a laboratory experiment that highlighted the potential promise of this approach, CRISPR was able to selectively target and kill MRSA in a heterogeneous bacteria population.
CRISPR-based antibiotics have the potential to be particularly transformative in an era of heightened infectious disease surveillance by bridging the gap between disease detection and clinical intervention. The dramatic decrease in the cost of genetic sequencing and increased adoption worldwide has allowed for the rapid detection and identification of new superbugs such as Carbapenem-resistant Enterobacteriaceae (CRE) that are becoming resistant to our most powerful antibiotics. These virulent and pathogenic Gram-negative bacteria have cell walls that are difficult for antibiotics to penetrate and innate cellular mechanisms to resist the effects of conventional antibiotics; recently, a woman in the United States died from a CRE infection that was resistant to all Food & Drug Administration (FDA) approved antibiotics. With CRISPR-based antibiotics, epidemiologists can detect emerging drug-resistant bacteria, sequence their genomes, and provide the information to scientists to develop a customized CRISPR construct that sensitizes these potential threats to existing antibiotics, preventing the spread of resistance.
What truly makes CRISPR-based antibiotics disruptive is its potential to reduce the costs of treating antibiotic resistance. CRISPR is a highly inexpensive, cost-effective tool that is increasingly being used throughout the scientific community. In fact, the components needed to conduct CRISPR gene editing experiments in the laboratory cost as little as $30. CRISPR can help to contain rapidly growing healthcare costs worldwide by increasing the potency of existing, widely available antibiotics, reducing the need for expensive and often fruitless drug discovery efforts. Even when new antibiotics make it to market, they are often priced out of reach for individuals in the developing world, creating serious access issues for the most vulnerable populations. CRISPR will continue to become more inexpensive with the commoditization of the necessary inputs, facilitating the adoption of this approach worldwide.
The cost savings realized by the implementation of CRISPR-based antibiotics can have tremendous impact as countries struggle to contain growing healthcare expenditures. Without further intervention, the World Bank projects that antibiotic resistance will result in an increase of $300 billion to $1 trillion in annual healthcare costs worldwide. Excess healthcare costs attributed to antibiotic resistant infections have been estimated to be $20 billion annually in the United States, at a cost of over $21,000 per infected patient. CRISPR-based antibiotics are well-suited to treat costly multiple drug-resistant bacterial infections, reducing the length of hospital stays related to the treatment of these infections and overall healthcare resource utilization.
The impact of CRISPR-based antibiotics is not only limited to treating bacterial infections in humans; this approach may have just as significant of an impact in mitigating antibiotic resistance in livestock as well. At a time of growing demand for animal protein throughout much of the developing world, antibiotic resistance is projected to cause a decrease in global livestock production of 2.6 to 7.5% by 2050. The amount of antibiotics used for food animal production is nearly four times greater than the amount used for medical treatment in humans, accounting for just under 80% of annual antibiotic usage in the United States. Many of the antibiotics used for treating bacterial infections in livestock are medically important for humans; the overuse of these antibiotics can create reservoirs of antibiotic resistance genes in livestock that can be acquired by bacteria that cause human disease. As a result of these effects, the FDA has recently banned the use of “medically important” antibiotics in livestock.
CRISPR-based antibiotics can obviate the need for the usage of medically important antibiotics in livestock altogether. This approach can restore the effectiveness of existing livestock antibiotics such as tetracycline that are less commonly used in humans and that bacteria have gradually acquired resistance to. CRISPR-based antibiotics can be applied to virtually any organism, allowing for widespread application of this approach throughout the livestock industry. What’s more, the use of CRISPR-based antibiotics can not only reduce the usage of antibiotics in livestock, but also greatly reduce the risk of foodborne illnesses from the presence of antibiotic resistant pathogens in meat and poultry. Consequently, CRISPR-based antibiotics can help address the challenge of antibiotic resistance from several different angles.
Although CRISPR-based antibiotics are an extremely promising solution to the antibiotic resistance crisis, several issues will need to be addressed to accelerate their development. Although CRISPR has high specificity, there may be off-target effects if the selected sequence to be edited appears in other parts of the genome. In addition, there may be unknown side effects of gene editing technologies in humans that may foment public resistance towards CRISPR-based antibiotics. However, the most pressing issue inhibiting the further development of CRISPR-based antibiotics is the delivery of CRISPR into human cells. Viral vectors have emerged as potential delivery systems due to their safety and efficiency; however, viral vectors have many limitations, including adverse immune reactions and size constraints. New non-viral delivery vectors such as liposomes and nanoparticles hold promise in addressing some of these limitations. With growing scientific acceptance of gene therapy as an approach for treating human disease, new research may help to address safety issues related to the use of CRISPR in humans and elucidate superior approaches for its delivery. Chinese scientists have already begun testing CRISPR in cancer patients and a first in human CRISPR trial has been approved in the United States. Regulatory agencies including the FDA and the European Medicines Agency have called for increased flexibility in regulating the clinical development of antibiotics for infections with limited treatment options, making the possibility of CRISPR-based antibiotics even closer to reality.
It is clear that innovative solutions for the antibiotic resistance crisis are needed immediately as we struggle to control the spread of resistance worldwide. Antibiotics are some of society’s most valuable resources that we simply cannot afford to lose. The discovery of antibiotics was one of the key factors that led to the dramatic increase in life expectancy over the 21st Century; antibiotics have been estimated to have increased average lifespans by up to 10 years. The presence of a robust armamentarium of cost-effective antibiotics is crucial for us to continue to make economic development gains across the globe. The discovery of penicillin by Alexander Fleming ushered in a medical renaissance that dramatically improved global public health and also fostered economic development worldwide. CRISPR-based antibiotics can help usher in the second wave of this renaissance, helping to create a future in which antibiotic resistance is no longer one of our most pressing public health challenges and improve the lives of millions worldwide. In summary, CRISPR-based antibiotics are an investment in the human capital of tomorrow. CRISPR has made gene editing universally accessible throughout the scientific world, but its application in solving antibiotic resistance may provide its greatest and most enduring value to our society.