Antibiotics are metabolites produced by microorganisms such as fungi, actinomycetes, or bacteria that have bactericidal or antibacterial activity. The earliest antibiotic, penicillin, was accidentally discovered by British bacteriologist Fleming in 1929. It saved the lives of millions of soldiers during World War II. Fleming himself was awarded the 1945 Nobel Prize in Physiology and Medicine. Over half a century since then, humans have discovered nearly 10,000 antibiotics in succession, bringing the gospel to the treatment of bacterial infectious diseases.
However, due to the widespread or inappropriate use of antibiotics and changes in the sensitivity of pathogenic bacteria to antibiotics, empirical antibiotic treatments are often difficult to achieve.
In 1961, methicillin-resistant Super Staphylococcus aureus MRSA was discovered in the United Kingdom.
In 1986, vancomycin-resistant Super Enterococcus VRE was discovered in France and the United Kingdom.
In 2009, an NDM-1 super-resistant enterobacteria emerged in India that could become resistant to almost all antibiotics …
The emergence of various new multi-drug resistant bacteria and even super bacteria has forced bacteriologists to face the fact that the evolution of drug resistance in bacteria may have far exceeded the development cycle of new antibiotics. Is humanity really about to fall into a dilemma? To answer this tricky question, we need to understand why bacteria develop resistance and how to use antibiotics appropriately.
Bacteria’s “self-help”-why has it become stronger?
Bacterial resistance is also called drug resistance, which refers to the resistance of bacteria to the action of certain antibiotics. The significance of monitoring bacterial resistance is to guide clinicians in the rational choice of antibiotics and to predict the effectiveness of antibacterial treatments.
▲ Evolutionary strategies for bacterial resistance
Bacterial resistance is divided into natural resistance and acquired resistance. According to Darwin’s theory of evolution, mutations in genes are completely random, and nature will provide selection pressure for these mutated genes. In the long evolution of bacteria, the results of each random mutation of genes gradually accumulate, eventually causing various drug-resistant genes to appear in the gene pool of bacteria, which is the natural resistance of bacteria. When people use a certain kind of antibiotics for a long time, antibiotics provide selection pressure to the flora, making the antibiotic-resistant strains gradually dominate, and the antibiotic treatment effect will gradually decline. Natural resistance generally targets only one or two similar antibiotics and does not play a major role in bacterial resistance.
What deserves people’s attention is acquired resistance, that is, the resistance caused by bacteria to obtain foreign gene fragments through conjugative plasmids, transformation, transduction, or genetic recombination under selection pressure. In this case, the resistance genes of bacteria can be transferred between different strains across species, which can easily lead to multi-drug resistance. Super bacteria, which are supposed to resist most antibiotics, have evolved in this way. However, acquired resistance is not stable, and bacteria may also lose resistance due to the loss of resistant gene fragments.
▲ Biochemical mechanism of bacterial resistance
In the long-term struggle with antibiotics, bacteria fight back against humans through these two evolutionary methods. The history of human antibiotic discovery has also become a history of the evolution of bacterial resistance. The specific biochemical mechanism of bacterial resistance is also wonderful, it is a living “Sun Tzu’s Art of War”.
▲ Penicillin resistance
The earliest star product in the antibiotic industry, its mechanism of action is to interfere with the synthesis of bacterial cell walls, thereby killing it. Staphylococcus, Neisseria gonorrhoeae, and other bacteria have evolved a β-lactamase against penicillin. This β-lactamase is like a sharp blade, which can be cut into with one hand and cut off the β-lactam ring in the molecular structure of penicillin. It can be directly hydrolyzed to lose its antibacterial activity. Streptococcus pneumoniae will go awry. It will change the penicillin-binding protein on its own cell wall, encoding a new low-affinity protein, which prevents penicillin from binding to the cell wall and thus cannot function. In layman’s terms, he is “disguised” like an agent, disguising himself and making penicillin unrecognizable.
▲ Chloramphenicol resistance
The bacteriostatic broad-spectrum antibiotic chloramphenicol can act on the 50S subunit of bacterial ribosomes and hinder the synthesis of bacterial proteins. Haemophilus influenzae evolved an inactivating enzyme. This inactivating enzyme, like the “spy” sent by the bacteria, breaks into the enemy, combines with the chloramphenicol molecule, and performs the molecular structure of chloramphenicol. “Reform”, the chloramphenicol modified by the inactivating enzyme loses its activity and cannot bind to the 50S subunit of the bacterial ribosome, thereby failing to exert its efficacy.
▲ Other drug resistance strategies
In the face of tetracycline, some E. coli bacteria will “lost their lives” and throw away a protein OmpF on their outer membrane, causing the outer membrane permeability to decline, making tetracycline unable to enter the bacteria through the outer membrane, thereby achieving “defend the enemy from the country” Outside “. Pseudomonas aeruginosa discards outer membrane protein D2, making it resistant to imipenem. In contrast, Staphylococcus aureus evolved a special drug pumping system for quinolone. As soon as the drug entered the bacteria, it turned on the motor to “repatriate” it.
Drug sensitivity test of one foot high and one foot high
Since bacteria are prone to drug resistance, why do clinicians choose to use drugs? It depends on the drug sensitivity test. When we are hospitalized for a bacterial infection, we often hear doctors saying that we need to perform a drug sensitivity test. So, what is a drug sensitivity test? What is the effect of drug sensitivity tests?
The so-called drug sensitivity test is an abbreviation for antibacterial drug sensitivity test. The significance of the drug sensitivity test is that it can predict the effect of antibacterial treatment. When the susceptibility test result is “sensitive”, the treatment may be effective, and when the test result indicates “resistance”, the treatment with the drug is definitely ineffective. Therefore, drug susceptibility testing plays a role in guiding clinicians to choose antibiotics. When the doctor finds that the drug susceptibility test result is “resistance”, the drug should be changed immediately to ensure the treatment effect. In addition, the drug sensitivity test also plays a role in monitoring the drug resistance of bacteria, analyzing and grasping the variation law of drug-resistant bacteria, and controlling and preventing the spread of drug-resistant bacteria.
“Upgrade” of antibiotics
——Precisely combat bacteria
The emergence of super bacteria has sounded the alarm for human beings. At present, the abuse of antibiotics has penetrated into all walks of life in the society. Each of us is a victim of antibiotic abuse, and we all blame the current situation of antibiotic abuse. In 2015, the United States took the lead in proposing the concept of “precision medicine”, which aims to find precise targets for treating diseases, so as to formulate personalized treatment plans, reduce the burden for patients, and improve medical benefits. In 2016, China also launched a precision medical plan.
▲ Precise medication
The so-called precision medicine refers to the use of high-throughput gene sequencing, big data analysis, and other means to establish a more precise personalized medicine based on individual genes, environment, and lifestyle. For the treatment of infectious diseases, the precise use of antibiotics is the key to achieving precision medicine.
Currently, antibiotics are mostly used by doctors based on experience. However, empirical medication cannot be 100% effective. Once encountering drug-resistant bacteria, or the drug used is not sensitive, empirical treatment will be invalid. As a result, we sometimes find that antibiotics have been prescribed in the hospital for several days, but that doesn’t work. The precise use of antibiotics refers to the selection of sensitive drugs based on quantitative drug susceptibility test results and pharmacokinetic models, and at the same time, accurate medication with appropriate methods, appropriate doses, and appropriate times to avoid unnecessary medication, and at any time Pay attention to the contraindications, adverse reactions, interactions, etc. of this drug in order to achieve the purpose of safe, reasonable, effective and economical medication. Therefore, promoting the accurate use of antibiotics is the main way to resolve the contradiction between antibiotic abuse and bacterial resistance.
▲ Livestock breeding
The abuse of antibiotics in farmed animals is much more serious than in humans. In 2008, a study in the Netherlands linked antibiotic abuse in livestock with zoonotic diseases. The abuse of antibiotics in animal husbandry not only promotes the spread of super bacteria, but antibiotics remaining in animals can also accumulate in the human body, causing the human body to be affected by various chronic toxic and side effects. Under the guidance of precision medicine, farmers should accurately understand and master the efficacy and dosage of each antibiotic, prioritize the use of narrow-spectrum antibiotics and alternate use of different antibiotics, strictly abide by the withdrawal regime, and stop using antibiotics before slaughtering or fishing. So that the animals can fully metabolize the antibiotics in the body.
▲ Primary medical institutions
Precision medicine puts forward new requirements for medical workers and managers of medical institutions: one is to improve professional quality and professional level. Making accurate diagnosis is a prerequisite for implementing precise treatment, and clinical medication should be adjusted according to the etiology diagnosis and drug sensitivity results. The second is to standardize the rational drug management system in primary medical institutions, increase supervision and publicity, encourage prescription doctors to customize personalized drug delivery mechanisms for patients, and choose sensitive antibiotics.
▲ Ordinary patients
For our people, a rational view of antibiotics is the key to the rational use of antibiotics. Antibiotics are not a panacea. Not all common colds or diarrhea are needed. Antibiotics should not be considered a flood beast. They are firmly resisted in all cases. China’s Food and Drug Administration stipulated as early as 2004 that antibiotics are prescription drugs and must be used under the guidance of doctors and pharmacists. Concepts such as self-medication, preventive medication, and standing antibiotics are not worth promoting.