How to solve the problem of overuse of antibiotics? We want to find an alternative

Produced by: Science Popularization China

Author: Yu Yajing, Feng Jie (Institute of Microbiology, Chinese Academy of Sciences)

Producer: China Science Expo

Editor's note: In order to unveil the mystery of scientific work, the China Science Popularization Frontier Science Project launched a series of articles called "Me and My Research", inviting scientists to write articles themselves, share their scientific research experiences, and create a scientific world. Let us follow the explorers at the forefront of science and technology and embark on a journey full of passion, challenges, and surprises.

In 2019, approximately 4.95 million people died from drug-resistant bacterial infections worldwide, of which 1.27 million cases were directly related to antibiotic resistance. Drug-resistant bacterial infections have become the third leading cause of death worldwide after ischemic heart disease and stroke.

Since the advent of antibiotics in the 20th century, they have become a powerful weapon for humans to fight against pathogens, and the average human life span has been extended by more than 20 years. However, with the intensification of the problem of antibiotic resistance (AMR), humans are facing new challenges in their fight against pathogens.

On the one hand, AMR makes more and more infections (such as pneumonia, tuberculosis and gonorrhea) difficult to treat . If there is no effective solution, it is estimated that by 2050, it will cause more than 10 million deaths each year, and antibiotic resistance will surpass cancer to become the leading cause of death in humans.

On the other hand, AMR can also lead to repeated and prolonged hospitalizations, resulting in a heavy burden of medical expenses. It is estimated that by 2030, AMR may reduce global GDP by at least US$3.4 trillion per year, causing about 24 million people in the world, especially in developing countries, to fall into poverty. If not effectively controlled, AMR may trigger a global public health and socioeconomic crisis.

To address the risk of antibiotic resistance, the United Nations specifically emphasized "good health and well-being" in its 17 Sustainable Development Goals (SDGs) and included AMR monitoring indicators, including bloodstream infection monitoring of specific drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli (3GC).

The World Health Organization (WHO) proposed the "Global Action Plan on Antimicrobial Resistance" in 2015, and issued the "Strategic and Operational Priorities for the Human Health Sector to Response to Drug-Resistant Bacterial Infections 2025-2035" guide in 2023.

In addition to antibiotics, there are natural bactericides in nature.

Scientists are also actively looking for microbial solutions from microorganisms. Bacteriophages (phages for short) are a type of virus that eats bacteria and are natural bactericides.

The earliest discoverer of bacteriophages was Dr. Federick William Twort from the United Kingdom. He observed that there were some mysterious substances in the culture dish that could kill Staphylococcus aureus, so he boldly speculated that it might be viruses or other organisms that ate these bacteria.

He published his findings in 1915, but they attracted little attention.

In 1917, French scientist Félix d′Hérelle also observed these mysterious substances that could kill bacteria. He observed that some life forms formed some "transparent spots" on bacterial culture media by killing bacteria, so he named these life forms "bacteriophage" and began to use bacteriophages to treat human bacterial infections with great success.

He was also nominated for the Nobel Prize many times, but unfortunately he did not win the award in the end.

The next 20 years were the first small boom in phage research, with researchers and clinicians quickly investing in phage treatments for bacterial infections. In an era when antibiotics were more valuable than gold, phages were widely used as antibacterial therapeutics.

Bacteriophages, like this computer-simulated phage, can clear infections in ways that antibiotics sometimes can't.

(Image source: https://www.popsci.com/health/antibiotic-resistance-phage-therapy/)

In the era of antibiotics, the application of phages is limited due to their specificity . To kill a specific target microorganism, a specific phage is needed, which is equivalent to a key opening a lock. If the right phage is not found, it will be difficult to treat the corresponding bacterial infection. Finding a suitable phage is time-consuming and costly, which has led to the gradual neglect of phage treatment options.

As the problem of antibiotic resistance becomes increasingly serious, bacteriophages have regained attention.

One of the most sensational cases was that in 2020, Professor Tom Patterson of the University of California, USA, was unfortunately infected with the "super bacteria" Acinetobacter baumannii while traveling in Egypt. All drugs could not control the serious systemic infection. His wife Steffanie Strathdee, director of the University of California, San Diego Global Health Institute and infectious disease epidemiologist, successfully cured her husband's infection using bacteriophages, the "natural enemy" of bacteria. This case promoted the development of phage therapy.

For wider application, gradually engineered phages

As we have said before, the specificity of phage is a double-edged sword. While ensuring the host specificity of phage, it also limits the host range of phage. So, is it possible to give phage the ability to recognize different types of hosts through artificial design?

If this can be achieved, we can make the phage attack wherever we point it!

The exciting thing is that we have now partially mastered this technology. Scientists call this modified phage "engineered phage."

Scientists have genetically modified bacteriophages so that the engineered phages have more diverse functions, such as changing the host range of phages or enhancing their antibacterial effects. This is like giving phages a more powerful weapon, enabling them to better kill bacteria.

The Institute of Microbiology, Chinese Academy of Sciences, where I work, has set up a special research group on pathogen resistance and bacteriophage control to conduct research in this direction.

The team I lead focuses on the drug resistance of pathogens and phage control, studying drug resistance mechanisms, new drug resistance genes and their spread, aiming to provide a theoretical basis for controlling bacterial resistance . At the same time, we explore bacteriophages that can eliminate multi-drug resistant bacteria and reveal their interactions with pathogens in order to find new prevention and control strategies.

Wu Linhuan's team is committed to the mining and utilization of microbial genome data, aiming to improve the efficiency of microbial resource development and promote the development of synthetic biology. In order to solve the problem of bacterial resistance, the two research groups hit it off and used synthetic biology strategies to transform bacteriophages so that bacteriophages can kill different bacteria.

Phage therapy is a new direction to fight bacterial resistance. In this process, receptor binding protein (RBP) plays a key role. You can think of it as the "door key" of the phage. It is located at the tail of the phage and recognizes and binds to the receptor on the surface of the bacteria like an antibody. This is the first and crucial step for the phage to successfully infect bacteria.

In order to address the problem of drug resistance, our research team isolated 114 phages from sewage samples in different regions and tested their lysis effects on 238 strains of Klebsiella pneumoniae. By studying the host range and genome of these phages, we found receptor binding proteins for different types of Klebsiella pneumoniae, just like we have built an "arsenal" to select suitable weapons for different bacteria.

However, there are many types of phages, and there is no perfect standard to evaluate them. To solve this problem, researchers cleverly selected a phage as a universal chassis, allowing it to carry receptor binding proteins for different pathogens and kill them.

After testing and experimental verification, it was shown that the host range of such engineered phages is consistent with its receptor binding protein, and it also shows the ability to lyse clinical strains. In this way, our researchers can customize engineered phages for different pathogens, thereby implementing precise killing.

For example, in customized drug delivery systems , researchers can allow engineered phages to carry antibiotics or other drugs and release them to specific bacteria. For example, phages are designed to carry antibiotics and accurately target the infection sites of drug-resistant bacteria, releasing drugs at the right time and place. This method can greatly reduce the side effects of drugs and improve the corresponding treatment effects.

Another example is environmental monitoring and biosensors . Engineered bacteriophages can be modified to emit light or change color in environments where specific bacteria live. By adding such bacteriophages to water samples, if specific bacteria are present in the water, the bacteriophages will infect and lyse these bacteria, thereby generating visual signals (such as luminescence or color changes) in the water sample, which can be used to quickly detect bacterial contamination of water quality. This has important application value in public health and environmental monitoring.

Conclusion

The new method developed by our team simplifies the development process of synthetic phage therapy and provides a standardized platform to help researchers quickly design phages suitable for specific bacteria. This means that in the future we can deal with various drug-resistant bacteria more efficiently and accurately. In addition, this standardized platform will also help standardize the regulatory process to ensure safety and effectiveness, thus paving the way for the promotion and application of phage therapy.

Next, our team will conduct epidemiological surveys and analyses of various pathogens prevalent around the world, summarize and conclude the prevalence of pathogens in various regions, and evaluate the development trend of pathogens to provide effective information for the expansion of precision phage therapy. Since bacteria will also respond to phages and resist the killing of phages, we will make the phage chassis safer and more efficient through reasonable design and modification, and enable it to carry more powerful weapons to treat infections caused by pathogens.