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"My child has never used azithromycin, so how come he has become resistant to it?" In early August this year, at the Lianqian Street Community Health Service Center in Siming District, Xiamen City, Fujian Province, parent Li Hua expressed his doubts to the doctor.

In pediatric clinics, parents of sick children frequently ask doctors this question. In fact, not only children, but many people are troubled by this problem.

Microbial resistance, especially bacterial resistance, has been listed by the World Health Organization as one of the public health issues that pose a serious threat to human safety.The increase and spread of multidrug-resistant bacteria has made standardized treatments ineffective.

"The environment is a reservoir of drug-resistant genes and an important medium for the spread of bacterial resistance," said Zhu Yongguan, an academician of the Chinese Academy of Sciences and director of the Institute of Urban Environment of the Chinese Academy of Sciences, in an interview with reporters.Human activities such as the misuse of antibiotics, intensive farming and domestic sewage discharge are exacerbating the spread and transmission of drug-resistant genes in the environment, further exposing people to an environment contaminated by drug resistance.

Zhu Yongguan, an academician of the Chinese Academy of Sciences and director of the Institute of Urban Environment, Chinese Academy of Sciences, conducts relevant research in the laboratory. Image source: Institute of Urban Environment, Chinese Academy of Sciences

To address this urgent problem, scientists and public health experts are actively looking for solutions, and a "war without gunpowder" in the microbial world has already begun.

1

Why drugs fail

Antibiotics, as a key weapon against bacterial infections, have saved hundreds of millions of lives. However, clinicians around the world are now facing a growing problem:Drugs that once cured all diseases are beginning to lose their effectiveness against certain bacteria.

"For example, the first-line macrolide drugs used to treat mycoplasma pneumonia, whooping cough and other diseases have seen declining therapeutic effects year by year." After more than ten years of clinical observation, Zhang Hao, a doctor at Shanghai Children's Medical Center, found that in a considerable number of children, the efficacy of azithromycin treatment declined, the course of the disease was prolonged, and lung lesions continued to develop.

The root cause of this series of problems is antibiotic resistance.Antibiotic resistance refers to the ability of microorganisms to develop resistance to one or more previously effective drugs, that is, the microorganisms' sensitivity to drugs decreases, resulting in normal doses of antibiotics being unable to exert their due bactericidal effect, or even being completely ineffective.

Schematic diagram of the spread of antibiotic resistance genes in the environment.

"If antibiotics are compared to spears, bacterial resistance genes are equivalent to shields that can defend against antibiotic attacks," said Shen Chunmei, deputy chief technician of the Hospital Infection Management Department of the Fifth People's Hospital Affiliated to Fudan University.Bacteria have a strong ability to adapt to the environment, and the development of drug resistance is the result of natural selection during their evolution.The abuse of antimicrobial drugs by human society is accelerating the development of bacterial resistance, resulting in fewer and fewer antibiotics available for clinical use. This not only raises medical costs, but also increases the health risks of patients.

The latest report from the China Antimicrobial Resistance Monitoring Network shows that in the first half of 2023, the detection rate of drug-resistant strains showed an upward trend. Among them, the detection rate of Acinetobacter baumannii, which is listed as a "key pathogen" of antimicrobial resistance by the World Health Organization, has risen to 78.6%-79.5%, setting a new historical high. According to relevant data from the World Health Organization, in 2019, infection with drug-resistant bacteria directly caused 1.27 million deaths and indirect deaths reached 5 million; it is estimated that by 2050, there will be an additional 10 million direct deaths each year, which is equivalent to the number of people who died of cancer worldwide in 2020.

Dr. Margaret Chan, former Director-General of the World Health Organization, once said,With the continued increase and spread of multidrug-resistant bacteria, common infections can become deadly threats."This is not an exaggeration. When humans are faced with a dilemma where there is no medicine available, even a minor wound or respiratory infection can have fatal consequences," she said.

2

The natural environment becomes a "transit station" for communication

In recent years, how to solve the problem of drug resistance has become one of the major challenges facing the medical field. Related research focuses on the molecular genetic basis of drug resistance and the transfer mechanism, in order to gain a deeper understanding of how microorganisms or cells develop resistance, and then develop new drugs, drug combinations, therapies and alternative treatments to address the problem of failure of existing drugs.

It is worth noting thatResistance can develop even if an individual has never taken antibiotics."It is the bacteria that are resistant, not the human body." Zhang Hao further explained that the main body of drug resistance is the microorganism itself. In other words, the human body is only the host of new drug-resistant bacteria. This means that the emergence of drug resistance is not only related to individuals, but also closely related to the human group and the environment.

At the individual level, long-term improper use of antibiotics can lead to bacterial gene mutations, which in turn lead to drug resistance. Resistant strains spread through contact within a population, putting the entire population at risk of drug resistance.What is more easily overlooked is that the drug-resistant genes remaining in the environment will accelerate the generation and spread of drug-resistant strains.

In 2002, when Zhu Yongguan was tracing arsenic pollution in the soil, he accidentally discovered that there were also drug-resistant genes in animal feces in the soil. In pig farms and chicken farms, copper, zinc, arsenic and antibiotics are added to the feed to make the animals grow quickly and prevent them from contracting intestinal diseases. These heavy metals and antibiotic resistance genes are discharged into the environment through animal feces.

"Drug resistance genes are genetic information and can be copied."Zhu Yongguan was keenly aware that, unlike the chemical pollution he had studied in the past, biological pollution caused by the addition of antibiotics that led to bacterial resistance might be a more serious environmental pollution problem. Soon, Zhu Yongguan gradually shifted the focus of his research from arsenic to drug-resistant genes, as related research in this field was still blank internationally at the time.

"The drug-resistant genes in the environment are the same as those in medicine. They are both nucleotide sequences that encode drug-resistant traits. However, these drug-resistant genes can spread between 'humans-animals-environment' and may be transferred to pathogens, causing pathogens to form new or multi-drug-resistant phenotypes, thus affecting the efficacy of antibiotics and human health." Su Jianqiang, a member of Zhu Yongguan's team and a researcher at the Institute of Urban Environment, Chinese Academy of Sciences, introduced.

Previously,A lot of research has been conducted on drug-resistant genes in the medical field and animal husbandry.The research conducted by Zhu Yongguan's team mainly focuses on drug-resistant genes in the environment. Its complexity is reflected in multiple aspects such as the persistent retention, transmission and spread of drug-resistant genes in the environment.

“In the past, we mainly focused on the use of antibiotics in the medical field and animal husbandry, and ignored the problem of antibiotic residues in the environment.In fact, trace amounts of antibiotics can be detected in rivers, soil and even drinking water, and the natural environment has become a 'transit station' for the spread of drug-resistant genes. "Su Jianqiang said that the environment plays an important role in the process of bacterial resistance. Therefore, solving the problem of drug resistance should not only start from clinical treatment, but also expand the perspective to the environment to comprehensively deal with this problem.

3

Tracing the source of drug-resistant gene contamination

Where do the drug-resistant genes in the environment come from? How do they spread and diffuse?Revealing the formation and spread mechanism of drug-resistant genes in the environment is crucial to controlling the spread of drug resistance.

To answer this scientific question systematically, we must first understand the "family background" of drug-resistant genes in the environment. To this end, Zhu Yongguan's team conducted a large-scale sampling survey in China. The team collected soil samples from 152 cultivated land or forests in 26 provinces across the country; they also went to 32 sewage treatment plants in 17 cities across the country to carry out sampling work during the peak period of urban drainage in order to understand the distribution of drug-resistant genes in my country's water and soil.

Researchers are taking samples outdoors. Image credit: Institute of Urban Environment, Chinese Academy of Sciences

It is not easy to accurately "pick out" drug-resistant genes from soil and sewage samples.First, there are hundreds or even thousands of drug-resistant genes in the environment, and the microbial communities in soil and water are extremely complex. Drug-resistant genes exist in various microorganisms, which makes separation and identification extremely difficult. Second, traditional detection methods cannot accurately identify low-concentration or newly emerging antibiotic resistance genes, which limits the depth and breadth of drug-resistant gene research.At the same time, massive amounts of data require powerful bioinformatics tools to process in order to accurately interpret the types, abundance, and potential transmission patterns of drug-resistant genes.

How to quickly detect numerous drug-resistant genes in a large number of environmental samples has become a technical difficulty for the team to carry out research. To this end, the team built a high-throughput quantitative polymerase chain reaction (PCR) detection platform for drug-resistant genes. This platform can perform quantitative detection of more than 300 drug-resistant genes in one run, greatly improving the screening and quantitative analysis capabilities of drug-resistant genes. With the help of PCR technology, the platform can replicate specific DNA fragments in large quantities, making quantitative analysis faster and more convenient to meet the needs of scientific research.

"We found 128 antibiotic resistance genes that were present in more than 80 percent of the samples."Zhu Yongguan introduced.

The establishment of the detection platform enabled Zhu Yongguan's team to make rapid progress in the investigation: First, they found a clear positive correlation between human activities and antibiotic residues in the environment.In cultivated soils that are more disturbed by humans, the number and abundance of antibiotic resistance genes detected are significantly higher than those in forest soils.At the same time, the number of resistant genes detected in densely populated areas in central and eastern China was higher than that in sparsely populated areas. Second, intensive farms and sewage treatment systems were basically identified as the main sources of resistant genes in the environment.

"Every pill we throw away, or resistant microbes excreted by humans or animals after taking antibiotics, can enter the environment with waste."Zhu Yongguan explained that through the microbial circulation system, drug-resistant genes spread from point sources to the entire ecosystem, exposing people to an environment contaminated by drug resistance.

In this investigation,For the first time, researchers have obtained 20 drug-resistant genes that are commonly found in my country's environment.This is crucial to understanding the transmission pathways and potential risks of drug-resistant genes.

4

Biochar method blocks spread of drug resistance

After finding the source of drug-resistant gene pollution, the team further discovered that water reuse and composting would lead to the spread and enrichment of some drug-resistant genes in the soil. At the same time, they found thatLong-term application of sewage sludge and animal manure will increase the diversity and abundance of soil resistance genes.

The sludge from sewage treatment plants needs to be treated accordingly before it can be applied to the soil, and composting is the main treatment method."We originally thought that high-temperature composting could kill pathogens in sludge and reduce drug-resistant genes. However, when we studied the changes in drug-resistant genes during sludge composting, we found that drug-resistant genes increased in the later stages of composting."Su Jianqiang said, "We then explored the possible reasons, and this result prompted us to pay attention to the problem of drug-resistant genes in organic compost."

In fact, antibiotics and antibiotic resistance genes released by human activities share a microbial world with humans, animals, and the environment, and are spread through microbial cycles.

"The research team collected raw vegetable salad samples from multiple restaurants.It was found that for every 300 grams of raw vegetables consumed, people can ingest about 109 copies of antibiotic resistance genes。"Zhu Yongguan told reporters that this shows that vegetables irrigated with organic fertilizers containing resistance genes will also carry resistance genes. These genes will be transmitted to the human body through the food chain. He further explained that the microbial community in the environment is very complex. For example, 1 gram of soil contains about 1 billion microorganisms, and horizontal gene transfer occurs between them all the time. This process causes the transfer and spread of antibiotic resistance genes.

In order to solve the problem of the spread of drug-resistant genes caused by organic composting, the team has developed a targeted "biochar" soil pollution control method, which uses high temperatures of 600°C or above to carbonize pig manure or chicken manure to decompose the antibiotics and drug-resistant genes therein.This original achievement can turn animal manure into biochar before it enters the environment, thereby reducing drug-resistant gene pollution in the soil. Currently, the "biochar" soil pollution control method has left the laboratory and entered the production line, becoming a product sold around the world.

In June this year, the project "Formation and Spread Mechanism of Drug-Resistant Genes in the Environment" led by Zhu Yongguan won the second prize of the National Natural Science Award.This honor fully recognizes the team's achievements in the research of drug-resistant gene environmental pollution.

At present, in addition to the "biochar" soil pollution control method, the development of high-temperature composting technology, advanced water oxidation technology, electrochemical technology, etc. also provides effective means to control and reduce environmental drug-resistant gene pollution. In addition, phage therapy, as a natural biological reduction technology, brings new hope and prospects for reducing resistance genes in the environment.

5

There is still a long way to go to curb microbial resistance

As a new type of microbial pollutant, drug-resistant genes in the environment are increasingly attracting international attention. In 2016, the World Health Organization, the Food and Agriculture Organization of the United Nations, and others clearly pointed out that a global action plan should be launched to focus on the spread and diffusion of drug resistance in the "human-animal-environment" network.

In 2022, 13 departments including the National Health Commission, the Ministry of Ecology and Environment, and the Ministry of Agriculture and Rural Affairs jointly issued the "National Action Plan to Curb Microbial Resistance", emphasizing the importance of research on bacterial resistance in the environment, and requiring various government departments and industries to strengthen collaboration, starting from multiple fields, and launch a combination of measures to jointly respond to this challenge.

So,How to deal with the risk of microbial resistance?

"Control at the source, control during the process, and repair at the end."Zhu Yongguan said that to deal with the risk of microbial resistance, we must respond from three levels, namely, strictly control the use of antibiotics and sewage discharge at the source, control the spread of resistant genes in the process, and carry out repair and management at the end.

"After our research results were published, they received widespread attention at home and abroad." Su Jianqiang said that the relevant research papers published by the team have become cited hot papers for several consecutive years, and the relevant original results have prompted measures to be taken around the world. At the same time, based on the high-throughput quantitative PCR detection platform built by the team, the Chinese team has established extensive cooperation with peers in the UK, Germany, the US, Australia and other countries.

At present, scientists have conducted some basic research on drug-resistant genes in the environment and obtained certain data, but comprehensive and systematic research on drug-resistant genes in the environment is still insufficient.Where do drug-resistant genes come from, where do they go, what risks they pose, and what specific countermeasures should be taken are still areas that require systematic scientific research to answer.

"my country is one of the first countries to issue and implement the National Action Plan for Curbing Bacterial Resistance. Curbing microbial resistance has risen to the level of national security and major strategy and is no longer limited to a certain industry or a certain professional field." Li Dachuan, deputy director of the Medical Administration Department of the National Health Commission, once said that due to the large differences in service capabilities and management levels between different regions and medical institutions, the situation of microbial resistance remains severe and complex. It is necessary to further strengthen the management of the rational use of antimicrobial drugs, improve the ability of medical and animal health professionals to prevent and control microbial resistance, and enhance the level of awareness of microbial resistance in the whole society.

"Antibiotic resistance caused by waste discharge is the 'footprint' left by humans in the microbial world. What we need to do is to reduce this kind of 'footprint' as much as possible." Zhu Yongguan emphasized.The transition of drug-resistant genes to live bacteria and then to pathogens, complex pollution, and the interaction between the host and the microbiome are new challenges and new topics that people are currently facing. The "war" between scientific researchers and microbial resistance is still continuing.