What Is Involved in the Production of Antibiotics?

Antibiotics refer to a class of secondary metabolites produced by microorganisms (including bacteria, fungi, actinomycetes) or higher plants and animals that have anti-pathogen or other activities and can interfere with the development of other living cells. Chemical material. Commonly used antibiotics in clinical practice are extracts from microbial culture fluids and chemically synthesized or semi-synthesized compounds. ^[1]

The antibacterial or bactericidal effect of antibacterial agents such as antibiotics is mainly to kill the mechanism that "there is bacteria but not humans (or other animals and plants)", including four major mechanisms of action, namely: inhibition of bacterial cell wall synthesis and enhancement of bacterial cell membrane permeability Sex, interfere with bacterial protein synthesis and inhibit bacterial nucleic acid replication and transcription. ^[1]

Are antibiotics prone to cancer?

From the discovery of penicillin by Fleming in 1929 to the large-scale commercial use of penicillin in 1942. The emergence of antibiotics has helped humans solve many problems. All diseases such as tuberculosis and anthrax have been eliminated. Therefore, antibiotics are the guardians of human health.

With more antibiotics decreased resistance? More: The decline in resistance is actually the cause of the person. Many people take antibiotics for all kinds of illnesses. At the same time, due to lack of medical advice, the dosage is often inappropriate. Rather than killing the bacteria thoroughly, the bacteria became resistant. Over time, bacteria have become harder to kill, and it has become harder and harder to get sick.
Can antibiotics cause cancer? More: Although antibiotics cause cancer, it is still a double-edged sword. It achieves its purpose by acting on bacteria, but there are always some bacteria that are not killed, and generate drug-resistant genes, which accumulate in future generations, and clinical resistance is getting higher and higher. Once humans become infected, they will gradually move to a state where there is no medicine, so antibiotics must not be abused.

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Chinese name: antibiotic
Foreign name: antibiotic
nickname: Antibiotics

Function: Mainly treats infections caused by small pathogens, etc.
Species: Quinolones, -lactams, macrolides, etc. ^[1]
Other uses: Some antibiotics can be used for anti-tumor or immunosuppression

History of Antibiotic Discovery and Application

Antibiotic definition evolution

It has long been known that certain microorganisms have an inhibitory effect on the growth and reproduction of other microorganisms, and this phenomenon is called antibiotics. With the development of science, people have finally revealed the nature of the antibiotic phenomenon. Some substances with antibiotic effects have been found in some microorganisms. They are called antibiotics, such as penicillin produced by penicillium, and Streptomyces griseus. Streptomycin and so on. Later, the definition of antibiotics was further refined, that is, a class of chemicals produced by certain microorganisms in their lives and having the ability to inhibit or kill certain other pathogenic microorganisms. ^[2]

Because some of the antibiotics originally found had a killing effect on bacteria, antibiotics were once called antibiotics. However, with the continuous development of antibiotics, antiviral, anti-chlamydia, anti-mycoplasma, and even anti-tumor antibiotics have been found and used in clinical practice. Obviously, it is not appropriate to call antibiotics, so the name of antibiotics seems more in line Actually. ^[3]

The emergence of anti-neoplastic antibiotics shows that the chemicals produced by microorganisms have the function of inhibiting the proliferation or metabolism of cancer cells in addition to the effects of inhibiting or killing certain pathogenic microorganisms at first, so the definition of modern antibiotics It should be: a substance produced by certain microorganisms that can inhibit the proliferation of microorganisms and other cells. ^[3]

History of antibiotic discovery

In 1929, when British bacteriologist Fleming cultivated bacteria in a petri dish, he found that there were no bacteria growing around the colonies that grew from the penicillium that accidentally fell on the medium in the air. He believed that the penicillium produced some kind of chemical Substance, secreted into the medium, inhibits the growth of bacteria. This chemical was the first antibiotic to be discovered-penicillin. ^[4]

During World War II, Fleming and two other scientists, Flory and Chan, worked hard to finally extract penicillin to make materials and medicines to subdue bacterial infections. Because during the war, medicines to prevent infection from war wounds were very important strategic materials. Therefore, the United States places the development of penicillin on the same level as the development of the atomic bomb. ^[4]

In 1943, Zhu Jiming, a microbiologist who was still engaged in scientific research after the resistance to Japan, also isolated penicillium from long mold leather and made penicillin from this penicillium. ^[4]

In 1947, American microbiologist Waxman was found in actinomycetes and made streptomycin to treat tuberculosis. ^{[4] After} more than half a century, scientists have discovered nearly 10,000 antibiotics. However, most of them are too toxic, so fewer than a hundred medicines are suitable for treating human or livestock infectious diseases. Later it was discovered that antibiotics not only inhibit the growth of microorganisms, some maggots can inhibit the growth of parasites, some can weed, some can be used to treat cardiovascular disease, and some can suppress the human immune response, and then applied in During organ transplant. ^[4]

After the 1990s, scientists expanded the definition of antibiotics and gave them a new name: biopharmaceuticals. ^[5]

Antibiotic application history

In 1877, Pasteur and Joubert first recognized the potential of microbial products as therapeutic drugs, and they published experimental observations that ordinary microorganisms can inhibit the growth of anthracnose in urine. ^[2]

In 1928, Sir Fleming discovered penicillium, which kills deadly bacteria. Penicillin cured syphilis and gonorrhea without any noticeable side effects at the time. ^[2]

In 1936, the clinical application of sulfonamide opened a new era of modern antimicrobial chemotherapy. ^[2]

In 1944, a second antibiotic, streptomycin, was isolated at the University of New Jersey, which effectively cured another terrible infectious disease: tuberculosis. ^[2]

In 1947, chloramphenicol appeared, which mainly targeted dysentery and anthrax bacteria, and treated mild infections. ^[2]

Tetracycline appeared in 1948, the earliest broad-spectrum antibiotic. At the time it seemed that it could be used effectively without a diagnosis. In modern society, tetracycline is basically used only for livestock breeding. ^[2]

In 1956, Eli Lilly invented vancomycin, known as the last weapon of antibiotics. Because it has a triple bactericidal mechanism for G + bacteria cell walls, cell membranes and RNA, it is not easy to induce bacteria to develop resistance to them. ^[2]

In the 1980s, quinolones appeared. Unlike other antimicrobials, they destroy bacterial chromosomes and are not affected by resistance to gene exchange. ^[2]

The main classification of antibiotics

According to their chemical structure, antibiotics can be divided into: quinolone antibiotics, -lactam antibiotics, macrolides, aminoglycoside antibiotics, and so on.

According to their uses, antibiotics can be divided into antibacterial antibiotics, antifungal antibiotics, antitumor antibiotics, antiviral antibiotics, livestock antibiotics, agricultural antibiotics, and other microbial drugs (such as ergot bases with pharmacological activity produced by ergot bacteria, there are Contraction of the uterus) and so on.

Depending on the type, antibiotics can be produced in various ways. For example, penicillin is biosynthesized by microbial fermentation, and sulfa and quinolone can be produced by chemical synthesis. There are also semi-synthetic antibiotics, which are antibiotics made by biosynthesis Various derivatives made by chemical, biological or biochemical modification of molecular structure. ^[4]

Mechanism of antibiotic action

There are four main mechanisms by which antibiotics produce bactericidal effects, namely: inhibition of bacterial cell wall synthesis, interaction with cell membranes, interference with protein synthesis, and inhibition of nucleic acid replication and transcription. ^[6]

Antibiotics inhibit cell wall synthesis

The cell wall of bacteria is mainly composed of polysaccharides, proteins, and lipids, and has the important functions of maintaining morphology, resisting changes in osmotic pressure, and allowing substances to pass through. Therefore, inhibiting the synthesis of cell walls will cause bacterial cells to rupture and die; mammalian cells, because they do not have cell walls, are not affected by these drugs. The achievement of this effect depends on a protein of the bacterial cell wall, usually called penicillin-binding proteins (PBPs). -lactam antibiotics can bind to this protein to inhibit cell wall synthesis, so PBPs are also targets of this type of drugs point. Antibacterial drugs acting in this way include penicillins and cephalosporins, but frequent use will lead to increased resistance to bacteria. ^[6]

Antibiotics interact with cell membranes

Some antibiotics interact with the cell membrane of the cell to affect the permeability of the membrane, causing important substances such as salt ions, proteins, nucleic acids and amino acids to leak out of the bacteria, which has a fatal effect on the cell. However, the basic structure of bacterial cell membranes is similar to that of human cell membranes, so this class of antibiotics is toxic to humans. Antibiotics acting in this way are polymyxins and gramicidins. ^[6]

Antibiotics interfere with protein synthesis

Interfering with protein synthesis means that enzymes necessary for cell survival cannot be synthesized. Antibiotics that act in this way include formycin (actinomycin), aminoglycosides, tetracyclines, and chloramphenicol. Protein synthesis is performed on the ribosome, which is composed of 50S and 30S subunits. Among them, aminoglycosides and tetracycline antibiotics act on the 30S subunit, while chloramphenicol, macrolides, and lincomycin mainly act on the 50S subunit, which inhibits the initial reaction of protein synthesis and peptide chain extension. Process and stop the reaction. ^[6]

Antibiotics inhibit nucleic acid replication and transcription

Inhibiting the transcription and replication of nucleic acids can inhibit the function of bacterial nucleic acids, thereby preventing cell division and / or the synthesis of desired enzymes. Antibiotics acting in this way include nalidixic acid and dichloroacridine, rifampicin. ^[6]

Characteristics of antibiotic action

Antibiotics act directly on bacterial cells

Antibiotics can selectively act on specific links in the DNA, RNA and protein synthesis systems of bacterial cells, interfere with cell metabolism, hinder life activities or stop growth, or even die, unlike ordinary non-selective disinfectants or bactericidal agents. Agent. Its antibacterial activity is mainly manifested in three phenomena: bacteriostatic, bactericidal and lysolytic. ^[7]

Selective antibiotic spectrum

The effects of antibiotics are selective. Different antibiotics have different effects on different pathogens. The type of pathogens that are sensitive to an antibiotic is called the antibiotic's antibiotic spectrum (antibacterial spectrum). It only has antibacterial effect on a single species or genus. Such antibiotics are called narrow-spectrum antibiotics. Penicillin, for example, only inhibits Gram-positive bacteria. Not only has an effect on bacteria, but also has an inhibitory effect on chlamydia, mycoplasma, rickettsia, spirochaete and protozoa. This type of antibiotic is called a broad-spectrum antibiotic, such as the tetracycline family (chlorin, oxytetracycline, etc.) Positive and negative, rickettsia, and some viruses and protozoa have inhibitory effects. ^[7]

Effective concentration of antibiotics

Antibiotics are a physiologically active substance. Various antibiotics can generally act on pathogenic bacteria at very low concentrations, which is another major feature that distinguishes antibiotics from other chemical fungicides. The effective concentration of various antibiotics on different microorganisms varies. Usually, the minimum concentration (MIC) that inhibits the growth of microorganisms is used as the antibacterial strength of the antibiotic, referred to as the effective concentration. The lower the effective concentration, the stronger the antibacterial effect. Antibiotics with a lower effective intensity are effective concentrations above 100 mg / L, and antibiotics with a higher effective intensity levels are effective concentrations below 1 mg / L. ^[7]

Antibiotics have selective toxicity

Antibiotics are less toxic to humans, animals and plants than microorganisms and are called selective virulence. It has a specific antagonistic effect on sensitive microorganisms, and the effect is very strong, and the dilution of more than ten thousand times still has significant antibacterial and bactericidal effects. ^[7]

Antibiotic adverse reactions

Antibiotic allergic reaction

Adverse reactions caused by antibiotics are very common. The main cause of allergic reactions is the patient's physical constitution, the drug itself, impurities in the drug, or the drug's metabolites. Allergic types mainly include: anaphylactic shock; hemolytic anemia; serum disease and drug fever; untyped allergic reactions: clinical manifestations are rash, angioedema, fixed erythema, severe erythema, etc., such as Penicillins, tetracyclines, streptomycin and lincomycin. ^[8-9]

Antibiotic toxicity

Toxic reactions caused by antibiotics can cause changes in the body's function or tissue structure, leading to changes in the body's physiology and function. They are often related to the dosage and duration of the drug. Especially, drugs with a low chemotherapy index have a small safety range and are likely to cause toxic reactions . Mainly include: nervous system toxicity; ototoxicity, nephrotoxicity; liver toxicity; blood system toxicity; immune system toxicity; followed by gastrointestinal toxicity, cardiotoxicity, etc., causing patients with gastrointestinal Road reactions, arrhythmias, myocardial damage, etc. ^[8-9]

Antibiotic specific reaction

Atopic reactions occur in a small number of patients and are often related to genetic factors. The abnormal sensitivity to certain drugs due to congenital inheritance is basically consistent with the inherent pharmacological effects of drugs. Most of them are caused by the lack of an enzyme in the body, which hinders the metabolism of drugs in the body. For example, chloramphenicol and amphotericin B enter red blood cells, which can transform hemoglobin into denatured hemoglobin; and for patients with normal enzyme systems, such reactions do not occur. ^[8-9]

Antibiotic double infection

Large-dose or long-term application of antibiotics, especially broad-spectrum antibiotics. When sensitive bacteria are killed or suppressed, other insensitive bacteria take the opportunity to grow and reproduce in large numbers. The bacteria that cause the new infection can be parasites that are harmless to the body under normal circumstances. Due to changes in the flora, other harmless bacteria that can inhibit the growth of the bacteria are transformed into pathogenic bacteria after being killed by drugs, or they can also be It is a drug-resistant strain of primary infectious bacteria. Secondary infections that are more likely to occur when using broad-spectrum antibiotics are: Clostridium difficile enteritis, fungal enteritis, oral mold infections, candida albicans vaginitis, and other secondary infections. ^[8-9]

Reasonable use of antibiotics

Symptomatic antibiotics

The use of antibiotics should be selected according to the indications of antibiotics. The main selection principles are as follows:

Choose appropriate antibiotics according to the type of pathogenic bacteria, clinical symptoms of infectious diseases, and antibacterial spectrum of drugs.

Choose antibiotics based on the site of infection and pharmacokinetics. Antibiotics must exhibit effective bactericidal or bacteriostatic effects in the body, and must reach effective drug concentrations in the target tissues. Therefore, antibiotics should be selected based on the concentration of the antibiotics in the infection site and the maintenance time.

Select drugs according to the patient's physiology, pathology and immune status, because the above factors will affect the effect of the drug. Different patients have different antibiotics. Women during pregnancy and lactation should avoid using medications that cause malformations and affect newborn development. ^[8]

Antibiotic dosage and course of treatment

The dosage and frequency of antibacterial drugs should be appropriate, and the course of treatment should be sufficient; too small or short duration of treatment will affect the efficacy and cause bacteria to easily develop drug resistance. Excessive dose or the course of treatment will not only cause waste but also cause adverse reactions. ^[8]

Antibiotic prophylactic

The preventive application of antibiotics accounts for about 40% of the antibiotics used, but actually has a small number of valuable applications. The wrong use of antibiotics for viral infections may even cause drug resistance or secondary infections. Therefore, the application of preventive antibiotics must be strictly prevented. The antibiotics can be applied preventively in the following situations: benzathine penicillin, penicillin V, etc. are used to clear the throat and other parts of the throat and other streptococci to prevent the onset of rheumatic fever; in epidemic cerebrospinal When meningitis is prevalent, sulfadiazine can be used orally as a preventive medication; patients with rheumatic or congenital heart disease should be treated with penicillin to prevent infective endocarditis before oral and urinary tract surgery; In patients with tube inflammation, penicillin can be used to prevent gas gangrene during amputation surgery; metronidazole and gentamicin can be used to prevent anaerobic infection before colon surgery. ^[8]

Combination of antibiotics

The purpose of combined medication is to improve the effect of disease treatment, reduce bacterial resistance, reduce the incidence of adverse reactions, and expand the scope of antibacterial. However, it is necessary to strictly grasp the indications of combined use of antibiotics, such as mixed infections that cannot be controlled by a single antibiotic, such as peritonitis caused by abdominal organ damage; severe infections that cannot be controlled by a single antibiotic, such as severe infections such as sepsis and sepsis; Single antibiotics are not easy to penetrate into the infection site, such as tuberculosis infection; pathogens have not been identified for serious infections, etc. If long-term treatment, pathogens may cause resistance to occur, they must be used in combination. Specific combined principles can refer to relevant books or literature, or follow the doctor's advice. ^[8]

Harm of antibiotic abuse

Antibiotic bacterial resistance

The discovery and application of antibiotics by mankind is a major revolution for mankind. However, with the widespread use of antibiotics in the clinic, drug resistance soon emerged, which not only caused a crisis in the use of antibiotics, but also the emergence of " super-resistant bacteria " has once again seriously threatened human health. ^[1]

Medical researchers point out that approximately 50% of antibiotics are abused worldwide each year, compared with 80% in China. In countries such as China, India, and Pakistan, antibiotics are usually easily available without a prescription, which has led to the general public's abuse and misuse of antibiotics to a certain extent. Local doctors had to use more powerful antibiotics when treating patients, which once again led to the bacteria becoming more resistant. It is because of the abuse of drugs that the bacteria quickly adapted to the environment of antibiotics, and various " super bacteria " were born.

There are five main mechanisms of bacteria's resistance to antibiotics (including antibacterial drugs): to break down or inactivate antibiotics , that is, the bacteria produce one or more hydrolases or inactivating enzymes to hydrolyze or modify the antibiotics that enter the bacteria to make them Loss of biological activity; change the target of the antibacterial effect , that is, the structure of the target of the antibiotic (such as nucleic acid or nucleoprotein) changes due to the mutation of the bacteria itself or the modification of the bacteria to produce an enzyme. Can not play a role; changes in cell characteristics , that is: changes in the permeability of bacterial cell membranes or other characteristics prevent antibacterial drugs from entering cells; bacteria producing drug pumps pump antibiotics that enter the cells out of the cells , that is: Active transportation mode pumps drugs that enter the cell to the outside; changes metabolic pathways , such as: sulfa drugs and p-aminobenzoic acid (PABA), competing for dihydrogallic acid synthase and producing bacteriostatic effects. For another example, after multiple exposures to sulfa drugs, Staphylococcus aureus increases its own PABA output, which can reach 20 to 100 times that of the original sensitive bacteria. The latter competes with sulfa drugs for dihydrosulfonate synthetase, making the The effect decreases or even disappears. ^[1]

In addition, DNA contamination due to antibiotic abuse is another major factor contributing to the "superbug". The rapid growth of the types and numbers of bacterial resistance genes cannot be explained by random mutations in organisms. Bacteria can exchange genes not only within the same species, but also between different species, and can even obtain genes from the scattered DNA of the same dead species. Therefore, the rapid spread of drug-resistant genes among bacteria has further promoted the production of " superbugs ".

Antibiotics human hazards

Antibiotics can cause harm to the human body while killing pathogenic bacteria. The drug enters the stomach through the mouth, is absorbed into the blood through the intestine, and is delivered to various cells of the human body. Only the drugs that reach the lesion site can play a role in sterilizing the pathogenic bacteria. The drugs in other tissues do not have a bactericidal effect. Instead, the metabolites are excreted through the liver and kidneys, and have certain damaging effects on liver and kidney organs, such as chloramphenicol, lincomycin, tetracycline, erythromycin, etc., which need to be metabolized in the liver. ^[10]

In addition, many antibiotics such as penicillin and streptomycin can cause allergic reactions, such as anaphylactic shock, from mild rashes, fever to suppression of the hematopoietic system, and even damage the nervous system, such as the central nervous system, hearing, vision, peripheral Neurological diseases and neuromuscular blockade. ^[10]

Finally, the abuse of antibiotics may also cause imbalance in the flora and delay treatment of the disease. Due to the effects of antibiotics, the type and number of various bacteria in the normal flora will change. Severe flora imbalance can cause a series of clinical symptoms in the body. It is mainly seen in patients who have been treated with broad-spectrum antibiotics for a long time. The antibiotic-sensitive bacteria in the body are killed in large quantities, while insensitive bacteria such as S. aureus and white rosary Bacteria etc. take the opportunity to reproduce, causing pseudomembranous enteritis, Candida albicans pneumonia, etc., which is a so-called double infection in the clinic, which brings great trouble to the treatment of the disease and has serious adverse consequences. ^[10]

Antibiotic development prospects

Antibiotics are secondary metabolites produced by microorganisms (including bacteria, fungi, actinomycetes) or higher plants and animals that have anti-pathogen or other activities and can interfere with other cell developmental functions. Chemical material. Looking back on its development history, with the continuous development of microbial research, people have made more and more new discoveries.

With the widespread use and even abuse of antibiotics, the problem of antibiotic resistance to bacteria has become very serious, and antibiotic resistance is posing a threat to global health. Therefore, it is imperative to develop new antibiotics. New antibiotics based on different mechanisms are at different stages of development. In addition, due to the rapid development of biotechnology, the development of antibody drugs and antibacterial peptide drugs has become a new force in the field of antibiotics. The development of these new antibiotics is expected to provide a new way for the prevention and treatment of pathogenic microorganisms while solving clinical antibiotic resistance. ^[11]