Drug resistance of bacteria is a very familiar topic. Some primary school students know that the "prick" of some pathogenic bacteria may be resistant to antibiotics because of mutation. It is also based on the status quo that "everyone knows a little nouns, but few people really fully understand the truth". When people mention antibiotics, they will immediately think of "abuse" and "drug resistance". They are also cautious in using antibiotics and become a panicked bird. ?

However, the topic of bacterial drug resistance has not been clearly discussed so far, and drug-resistant fungi have made a grand appearance. 2065438+On April 6th, 2009, a fungus named "Candida" was reported in The New York Times, with the introduction of "deadly fungus, there is no cure". This fungus has appeared all over the world in just 10 years, and it is still expanding its territory. About half of the infected people died within 90 days, and the final mortality rate reached 60%. At present, there is still no specific medicine, and even the world's top medical institutions can do nothing. ?

Screenshot of The New York Times's report on deadly fungi?

So, when did this terrible mysterious fungus begin to appear? What is the motivation for their simultaneous appearance around the world? Is it antibiotics again this time? Will such a high mortality rate cause a serious disaster like the medieval Black Death? Behind the mystery, apart from lamenting the tenacious survival instinct of small creatures, the complex and subtle interaction between human beings and the environment and other creatures is really frightening. ?

Fungi? Bacteria? Virus? Don't be silly, can't you see?

Before the story of drug-resistant fungi begins, it is necessary for us to review three kinds of microorganisms we have learned in junior high school biology class. ?

First of all, structurally, viruses are the simplest, followed by bacteria, and fungi are more complicated than bacteria. If the virus is compared to a human flatbed, then the bacteria is at least an electric tricycle, and the fungus may have to be a car. ?

Secondly, all three may lead to human diseases and require different treatment methods. Most antibiotics are only for bacterial infections, viral diseases need antiviral drugs, and fungal infections also have corresponding antifungal drugs. ?

For example, because the virus has a simple structure, no cell wall and does not synthesize protein by itself, antibiotics that attack the cell wall or hinder the synthesis of protein cannot act on the virus. ?

In addition, not all antibiotics can target all kinds of bacteria, such as Pseudomonas aeruginosa, whose cell wall has a small opening, and many antibiotics cannot invade its interior, so the killing effect is limited. ?

Various antibiotics?

Finally, although all three have "enemies" that endanger human health, they also have indispensable allies in human life. Many kinds of fungi are indispensable in brewing and fermentation industry. Many bacteria play an important role in human digestion and material circulation in the biosphere. There are bacteriophages in the virus, which can help people to kill bacteria or help people to synthesize protein. ?

A super fungus: Candida auriculata?

Next, let's uncover the true meaning of drug-resistant fungus "Candida auricula". ?

Candida auricula can cause invasive candidiasis, such as candidemia, pericarditis, urinary tract infection and pneumonia. Because of its multiple drug resistance, high mortality and difficult diagnosis of infection, it is also called "super fungus". At present, the US Centers for Disease Control and Prevention has listed Candida auralis as an "urgent threat". ?

In 2005, Japanese organized scientific research forces to conduct a centralized survey of fungal communities in China. At that time, the medical staff of Tokyo Health and Longevity Medical Center collected samples from the ear canal of a 70-year-old Japanese woman. After years of analysis and identification, scientists found that this sample could not be classified as any existing fungi. Therefore, Japanese scientists reported this new fungus for the first time in 2009, and named it "Candida auricula". Unexpectedly, serious cases caused by Candida auricula infection broke out in many countries in Asia and Europe. ?

Candida albicans in Petri dishes?

The first case in the United States appeared on 20 13. At that time, a hospital in new york admitted a woman who complained of respiratory insufficiency. This 6 1 year-old woman, born in UAE, was found to be positive for Candida auricula one week after admission, and eventually died shortly after. However, in view of the fact that the influence of Candida auricularia was not as great as it is now, the hospital didn't report the situation until 20 16, when the US Centers for Disease Control and Prevention received a case report from the hospital. ?

What really brought Candida auricula into public view was the concentrated outbreak of infection in Royal Brompton Hospital in 20 16. At that time, the hospital had 72 cases of infection at a time, and the ICU was closed for two weeks. Because the seriousness of the situation was initially underestimated, the hospital did not disclose the situation in the hospital to the public at the first time. ?

However, according to the situation disclosed afterwards, a few months before the media intervened in the report on a large scale, the hospital had issued relevant alarms and tried to disinfect the area where the epidemic occurred. The staff used a special aerosol to spray hydrogen peroxide solution near the area where patients infected by fungi were treated. Theoretically, the steam of this spray will penetrate into every corner of the room. ?

These rooms were kept saturated with hydrogen peroxide for a week, and then the researchers placed a mirror in the center of the room to observe the growth of microorganisms in the bottom culture medium. The scary thing is that even so, there is still a Candida auricula community in the Petri dish. However, this incident was finally concealed by the hospital ...?

Only in the past five years, Candida auricula has appeared in hospitals in the United States, Spain, Venezuela, India, Pakistan, South Africa and even China, among which the large-scale infection in the University Hospital of Valencia, Spain is the worst. At that time, there were 372 cases of infection in this big hospital with 992 beds, among which 85 people developed candidiasis, and 465,438+0% of them died within 30 days. ?

Almost simultaneous outbreaks in many places: the mysterious origin of drug-resistant fungi?

Candida auricula was discovered in 2009. In just ten years, it has caused many deaths in many parts of the world. But what really bothers researchers is the mysterious origin of this fungus and its spread path around the world. In view of the earliest cases reported in Asia, scientists initially speculated that the strains appearing in Asia caused epidemics in other parts of the world. However, after comparing the genetic information of strains collected from South Asia, Venezuela, South Africa and Japan, the researchers were surprised to find that they belong to four independent branches and there is no genetic relationship between them. ?

Further comparison of gene sequences shows that these four branches were isolated from the same ancestor thousands of years ago and existed in the environment all over the world as harmless colonies until drug-resistant strains appeared at the same time about ten years ago. That is to say, Candida auricula, which is popular all over the world, actually appears in different places at the same time in an instant, and several strains have evolved independently in different places, so the possibility of parallel transmission between them is very small. What made them come out together as if they had an appointment? ?

Regional distribution map of candida auricula cases?

Unfortunately, the exact reason is still unknown. ?

Initially, researchers took the causes of drug-resistant bacteria as a reference, and naturally thought that the excessive use of antifungal drugs in clinical treatment was the main reason for the drug resistance of fungi. However, although there are not many kinds of drugs to treat fungal infections in clinic, the incidence of fatal fungal infections is actually very low, and the application scenarios and drug resistance of antifungal drugs are not as common as bacteria for the time being. ?

So, what if this pot doesn't let the abused antifungal drugs come back? What caused the sudden outbreak of Candida auricula? Although the exact answer is still unknown, pesticides used to kill plant fungi are probably the real reason behind it. ?

Your circle is too messy! Fungi, humans, antifungal drugs and pesticides love and kill each other?

Fungi may not only endanger the health of animals, but also endanger the normal growth of plants. In the process of crop planting, it is inseparable from the use of antifungal drugs. Crops such as potatoes, beans and wheat need to kill pathogenic fungi in the soil regularly. Different from the varieties of antibiotics, there are few kinds of anti-fungal drugs, most of which are azole compounds. Pesticides that kill plant fungi also contain structures similar to azole compounds, which leads to the possibility of drug resistance mutation of fungi living in natural environment under the action of pesticides. Once infected, antifungal drugs similar in structure to pesticides will not work. ?

In fact, human understanding of drug-resistant fungi has experienced a tortuous development process. ?

About 1997, a common fungus named Aspergillus fumigatus began to show drug resistance, and the mortality rate of pneumonia caused by drug-resistant Aspergillus fumigatus was as high as 60%. At first, medical workers naturally thought that the use of antifungal drugs during treatment was the cause of drug resistance variation of fungal strains, and the fact that the proportion of drug-resistant strains in the total strains was monitored during treatment seemed to confirm this guess. ?

However, in the course of the study, it was found that drug-resistant strains were also found in many patients who had never been treated with azole compounds, which indicated that drug-resistant strains existed at the beginning of fungal infection. ?

Based on this, researchers began to suspect that drug-resistant strains already existed in the environment, and subsequent experimental results confirmed this guess. ?

The researchers found drug-resistant strains in flower beds, grasslands and air conditioning systems around the hospital, and the proportion of drug-resistant strains in soil samples was as high as 12%. In addition, antifungal demethylation inhibitors (DMI) with similar structures to medical azoles account for one-third of the world pesticide market, and drug-resistant strains also show corresponding resistance to DMI pesticides. ?

Fungal colonies in Petri dishes, all samples come from soil?

Although these observations are not enough to conclude that the application of pesticides is the direct cause of fungal drug resistance, it can be concluded that there are a large number of drug-resistant fungi in nature, and their power is comparable to that of Candida albicans. Fungal infection originally mainly attacked people with low immunity. When the drug can work normally, the infection will be effectively suppressed soon. Once drug-resistant fungi appear, the limited choices in the "human arsenal" will be stretched, resulting in a high mortality rate of susceptible people. ?

Will new antifungal drugs find inspiration from pesticides?

In the future, in addition to further exploring the relationship between fungal drug resistance and antibacterial drugs and pesticides, it is also urgent for researchers to develop new antifungal drugs with different antibacterial mechanisms. ?

However, because fungi and human cells belong to eukaryotic cells, there are many connections between them, and drugs that kill fungal cells often harm normal human cells, so human beings can only design antifungal drugs from the limited differences between human cells and fungal cells. Unfortunately, most of these drugs can no longer effectively kill drug-resistant strains. ?

However, many scholars have suggested that human beings can actually seek inspiration from antifungal pesticides. This is because besides DMI, there are several insecticides that can effectively kill fungi and keep low human toxicity. However, quite a few of these pesticides are still in a state where the sterilization mechanism is not fully understood. It is a reasonable choice to find inspiration for drug design from these effective antifungal pesticides. ?

Edible fungi are also a kind of fungi?

In fact, drug resistance is a long-standing problem and an inevitable fate in various fields of chemotherapy, such as antibiotics, antiviral drugs, antifungal drugs, antiparasitic drugs and even anticancer drugs. We should understand that the game between human beings and microorganisms will be a long-term and escalating battle. In this process, it is necessary to use antibacterial drugs rationally and avoid drug resistance due to improper application of drugs. At the same time, we also need to bring the whole ecosystem where humans and pathogenic microorganisms live into the scope of research and discussion. ?

References:?

1. Mysterious drug-resistant bacteria regarded as an "urgent threat" are quietly sweeping the world?

2. What is the division of fungal infection?

3. Fungi are tolerant. そして in the future

4. The most resistant bacteria in history "infected, beaten, dead".