Can a drug be used to “eliminate” bacteria at a specific point? Does such a drug really exist?

In our impression, viruses are often the source of infection that causes diseases and even cancer. They are easy to mutate and have limited treatment methods, which makes people shudder. However, there is a type of virus that has been regarded by scientists as a promising drug for treating bacterial infections since it was discovered. That is bacteriophage.

Scientists studied and modified phages even before the antibiotics that are now widely used. Although progress is slow, phage therapy is gradually showing advantages that antibiotics do not have. They can play a role in diseases such as enteritis, sepsis, and infections in different parts of the body.

As the name implies, bacteriophages are a type of virus that uses bacteria as hosts. Bacteriophages can infect bacteria and replicate and multiply in them. Sometimes they can directly cause bacterial lysis, and the released phages will then look for the next host. Wherever there are bacteria, there are phages, and our bodies are no exception. In the bacterial flora of our skin, intestines and other parts, there are billions of phages parasitizing. One major feature of phage infection of bacteria is selectivity, and one phage can only infect one type of bacteria. If the microfilament protein of the phage happens to match the protein or lipopolysaccharide on the surface of the bacteria, it is like a key inserted into the keyhole, and the door of the bacteria will open to the phage. It is precisely because of this characteristic of phage infection of bacteria that it has an advantage that antibiotics do not have, that is, it is targeted when killing bacteria.

Commonly used antibiotics, such as penicillin, cephalosporin, tetracycline, etc., will kill a large number of bacteria when taken. Each time we are infected by only one or two pathogens, such as Staphylococcus aureus, but the indiscriminate attack of antibiotics will also destroy our own intestinal flora, truly achieving "killing one thousand enemies and injuring eight hundred of our own." Another thorny problem is that there are more and more drug-resistant pathogens, and antibiotics are completely ineffective against them because they are the survivors who have escaped from antibiotics. After screening with antibiotics, the non-resistant ones all died, while the resistant ones gradually grew stronger. Some pathogens can even escape the attack of multiple antibiotics, and we are helpless against these multi-drug resistant bacteria and can only rely on our own immune system to resist.

Multiple bacteriophages on rod-shaped bacteria, picture from Tuchong.com

Are there any successful clinical cases of phage therapy? In the United States, a 68-year-old patient developed a multidrug-resistant Acinetobacter baumannii infection near his pancreas. When multiple antibiotics failed to work together, the patient fell into a coma and was even at risk of death. The University of California, San Diego, which treated him, applied for the use of phage therapy and obtained FDA approval. In the end, the patient received a treatment containing 9 phages, which controlled the bacterial infection and gradually improved various physiological indicators. After 11 weeks of continuous treatment and 245 days of hospital observation, the patient recovered and returned home to work.

Another study that has just been published shows that a cocktail therapy consisting of a mixture of five bacteriophages can inhibit the reproduction of multidrug-resistant Klebsiella pneumoniae in pneumonia patients, thereby curing the pneumonia caused by it.

Since phage therapy can save lives, why hasn't it been used on a large scale in clinical practice? There are two main limitations to phage therapy. First, it is difficult to standardize phage therapy. Phage therapy often does not use a single phage, but a combination of several phages. Different combinations must be designed and optimized for different infections. If the wrong phage strain is selected in the combination, it will not work, and if too many are selected, it will be a waste. Therefore, the cost of research and development is relatively high, and standardization is even more difficult.

Second, phage therapy also has the problem of drug resistance. Since bacteria can escape the elimination of antibiotics, there must be bacteria that can resist phages. In some cases of treating patients, scientists have detected bacteria that can escape phage invasion. They change the structure of their own cell surface proteins to avoid bacterial binding. Some bacteria can also express enzymes that destroy the phage genome to achieve self-defense. Although bacteria want to escape, phages will not sit idly by. After all, they cannot survive without a host.

The structure of the receptor protein on the surface of the bacteria will change, and the protein fiber at the tail of the phage, which is the part used to bind to the bacteria, will change accordingly, and the two will co-evolve in a race against each other. In addition, some phages carry methyltransferases, which can protect their own genomes from being destroyed by host bacteria. These characteristics of phages and their ability to evolve rapidly have always made scientists full of hope for phage therapy. By utilizing their own characteristics and combining them with gene editing technology and other means, more stable and effective phage therapeutic drugs may be developed. Although the road ahead is still full of difficulties, in the face of the threat of super-resistant bacteria, humans may really need to seek help from phages, the smallest microorganisms, and invest more time and cost in the research and development of phage therapy.

This article is a work supported by Science Popularization China Starry Sky Project

Author: Zhao Bei

Reviewer: Tao Ning (Associate Researcher, Institute of Biophysics, Chinese Academy of Sciences)

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.