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🍴 | Pesticide-free, antibiotic-free, selected ingredients, seasonally


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No pesticides, no antibiotics, carefully selected ingredients, seasonally

 
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Antibiotics

Antibiotics(This is a substance,English: antibiotics) IsmicroorganismProduces and inhibits the growth of other microorganismsmaterialIs defined as.In a broad sense, other than semi-synthetic antibacterial agents that are chemically modified products produced by microorganisms, synthetic antibacterial agents that are artificially synthesized, and non-microorganisms such as tumor cells.細胞May contain substances that inhibit the growth and function of[1]..It also refers to drugs that utilize the action of antibiotics.Antibiotic agentsSometimes called.

Alexander Fleming 1928 ToBlue moldFound frompenicillinIs the world's first antibiotic.It took 10 years from the discovery of penicillin to its practical application, but once it was put into practical use,streptomycinAntibacterial drugs using antibiotics such as these have been developed one after another, revolutionizing human medicine.This is why the development of penicillin was one of the greatest discoveries of the 20th century and is sometimes referred to as the "miracle drug".[2].

It is said that there are tens of thousands of natural antibiotics, of which more than 200 have been used as antibacterial agents.[3]..However, abuse has been pointed out and more than 50% of antibiotic prescriptions are inappropriate, the OECD reports.[2].. WHO and the CDC in the United States have developed guidelines and are calling for their proper use.Japan's Ministry of Health, Labor and Welfare also released the first edition of the 2017 guidelines[4].Drug resistant bacteriaThere is a problem that causes the disease, and it is warned to use it even though it is not an infectious disease.[4].

Name and definition

Bacteria,FungusWhen two types of microorganisms such as these are present in an environment, the growth of one of them may be inhibited.Symbiosis This antagonistic effect, which is synonymous with (symbiosis)antibios(Antibiosis; Antibiotics-AntibioticsBoth[5])[6][7],As an exampleBlue moldIs known to suppress bacterial growth[8].Antibiotics (antibiotic) is a term that refers to a substance produced by a microorganism that has an antibiotic effect.[9], The above-mentioned inhibition of bacterial growth by PenicilliumAlexander FlemingIs an antibiotic found in PenicilliumpenicillinIs due to[10]..The word antibiotic was first defined as a type of antibioticstreptomycinAnd won the Nobel PrizeSelman WaxmanIs.He is in the 1940s[Note 1]"Produced by microorganisms and inhibits the growth of other microorganismsmaterialDefined the word antibiotic as the name[14]..However, this definition is premised on the use of antibiotics by humans, and the concentration of naturally occurring antibiotics is lower than the concentration at which the medicinal effect can be obtained, and no antibiotic action occurs between the producing microorganism and the surrounding microorganisms. It has been known[9][14]..On the other hand, antibiotics that selectively inhibit the metabolic system of bacteria and do not inhibit the metabolic system of the host are used as therapeutic agents for bacterial infections.[15].. According to 2012 estimates, it has been derived from 6 to 8 types of microorganisms so far.Natural compoundIs known, but 40% of them are said to have a function as antibiotics, and about 200-220 kinds of substances have been used for treatment as antibiotics directly derived from microorganisms.[3]..In addition, "antibacterial agents" are used as a general term for "drugs that act on bacteria and are used to treat and prevent infectious diseases", and "drugs that utilize the antibacterial action of antibiotics". As a common name forAntibiotic agentsThe term is used.However, antibacterial drugs, antibiotics, and antibiotics are used without strict distinction as a general term for drugs that have an effect on bacteria.[4]..Some antibiotics are used for purposes other than antibacterial drugs,Polyene macrolide systemNot bacteria likeFungusSubstances that are toxic to and used to treat fungal infectionsIvermectinHas antiparasitic activity in the substance on whichAvermectin, Has antitumor activity as well as "other microorganisms"Actinomycin,RapamycinSubstances that exhibit immunosuppressive and anti-inflammatory effects, such as, are also used as drugs derived from microorganisms.[16].

in recent yearsChemical synthesisProduced in or naturalDerivativeSome are semi-synthesized from[1]..Waxman defined substances produced by microorganisms as antibiotics, but there are also semi-synthetic antibacterial agents that are artificially modified from natural products, such as many β-lactam antibiotics and macrolide antibiotics. Called an antibiotic[12]..In addition, pyridone carboxylic acid type (Quinolone,New quinolone system) AndSulfa drugStrictly speaking, antibacterial substances that are completely artificially synthesized are not included in antibiotics and are called "synthetic antibacterial drugs", but they are sometimes treated as antibiotics.[14][12][17].

Incidentally,ethanol,GlutaraldehydeSuch asdisinfectant (disinfectant) also has the function of killing and inactivating microorganisms, but generally shows strong cytotoxicity and cannot be taken because it does not have selective toxicity, and is distinguished from antibacterial drugs including antibiotics.[18][19][20].

History

Pre-modern infectious disease treatment

In the world before the 20th century, the treatment of infectious diseases is exclusivelyTraditional medicineWas done by.Records of treatments with antibacterial substances have already existed since BC[21].Ancient egypt,Ancient greeceIn ancient civilized societies such asMoldAnd plants were used to treat infectious diseases[22][23]. Also,NubiaA large amount of tetracycline has been detected in the mummy.It is speculated that this is the accumulation of tetracycline derived from fermented foods produced at that time.[24]It has been pointed out that they may have been protected from infectious diseases by ingesting tetracycline through their diet.[25]..Some of the treatments that have been used for a long time have been verified to be effective, and medicines made by mixing vegetables, wine, and bile according to the recipe 1000 years ago are used.Methicillin-resistant Staphylococcus aureusIt was reported in 2015 that it was effective against[26][27]..The history of resistance to antibiotics is very old, and it is estimated that certain resistance genes existed billions of years before the discovery of antibiotics.[25][28].

Development of synthetic antibacterial agents

Prior to the discovery of antibiotics, it was known that microorganisms suppress the growth of other microorganisms.For example, in 1887Louis PasteurRagaAnthraxWe have discovered a phenomenon in which growth is suppressed when culturing with other aerobic bacteria.Also, in 1889, Jean Paul Vuillemin defined "a relationship in which one organism kills another for survival" as an antibiotic.[29].. In the 1890s, Pseudomonas aeruginosa extract was reported to be used in many patients, and is probably the world's first report on the clinical application of antibiotics.[26].

The history of modern antibacterial drugsSalvarsanDevelopedPaul EhrlichAnd discovered penicillinAlexander FlemingOften associated with two people[25]First, Erich et al. Discovered a synthetic antibacterial drug derived from a pigment[30][31][32]Introduced for the first time the concept of chemotherapy for infectious diseases based on selective toxicity[17][33]..Erich et al. Have little effect at the cost of serious side effects at the time.Inorganic mercury saltWas being treated bysyphilisTo develop a remedy forSahachiro HataTogether with them, they started what we call compound screening today in 1904.The 1909th compound, which they tested in 606, showed efficacy in rabbits with syphilis and laterHoechstSold as salvarsan by the company.Erich succeeded in developing salvarsan, and the improved version of neosalvarsan was the most prescribed treatment until the 1940s.[25][34]..The therapeutic drug development method using their screening was also applied to the development of other synthetic antibacterial drugs, and was developed as a pigment.ProntosilMay also be useful as a remedy for infectious diseasesGerhard DormakRevealed bySulfa drugVarious antibacterial drugs were discovered[25]..Domagk discovered the antibacterial properties of Prontosil in 1939.Nobel Prize in Physiology or MedicineHas been awarded[Note 2][35].

The Golden Age of Antibiotic Discovery and Antibiotic Research

1928 year 9 month 3 dayFlemingbypenicillinThe discovery of was made on the occasion of one failure,SerendipityAlso known as[25][10]..After the holidays, Fleming went to work at the workplace at that time and used the Petri dish that had been cultivated on the laboratory table.StaphylococcusMoldContaminationNotice that you are doing.At this time, Fleming observes that the contaminated mold suppresses the growth of surrounding bacteria, and this growth suppressionBlue moldI submitted a treatise that it was due to a substance produced by the substance and that the substance was named penicillin.[10][36].. afterwardsOxford University OfHoward FloryErnst Boris ChainWhen these studies enable mass production, Flory et al. Will conduct clinical trials of penicillin from 1941 to 1942.In this clinical trial, penicillin was extremely effective with no side effects.Penicillin became widely used after World War II, and in 1945, Fleming, Flory, and Chain were found by the discovery of penicillin and subsequent research.Nobel Prize in Physiology or MedicineHas been awarded[10].

The discovery of three antibacterial agents, salvarsan, prontosil, and penicillin, had a great influence on the subsequent development research of antibacterial agents, and antibiotic research reached its golden age from the 3s to the 1950s.[25].. At the end of the 1930sSelman WaxmanStarts Searching for Antibiotics[26].. Waksman, who defined antibiotics in the 1940s[12][11],tuberculosisEffective forNeomycin,streptomycinDiscovered many antibiotics[26], The Nobel Prize in Physiology or Medicine was awarded in 1952 for its contribution.[37].

The discovery of antibiotics in this era was accomplished by screening the soil to find useful microorganisms.As a result, pharmaceutical companies of this era are collecting soil samples from around the world.for exampleerythromycinTo produceActinomyceteIt is,Eli Lilly and CompanyDiscovered in the garden in 1949 by a Filipino doctor hired by[38]..Actinomycetes are known to be the major antibiotic-producing microorganisms, with 1945% of the antibiotics discovered between 1978 and 55 derived from actinomycetes.[26]..As a new line of antibiotics and synthetic antibacterial agents discovered and developed in this eraAmino glycoside,Cephalosporins,Chloramphenicol,tetracycline,Macromide,Quinolone,TrimethoprimAnd so on.Some researchers who have reached the golden age of antibiotic development have hoped to overcome infectious diseases, but since then, few new strains of antibiotics have been discovered, while emerging infectious diseases have been around since the 1990s. And the problem of drug resistance became bigger[39].

Emergence of resistant strains and new approaches

As mentioned above, resistance to antibiotics existed before humans used antibiotics.For example, the first bacteria registered as a standard strain in the United Kingdom was registered in 1915.ShigellaHowever, the strain was revealed in 2014 to have resistance genes to penicillin and erythromycin.On the other hand, it is known that the use of antibiotics in human agriculture and medicine has increased resistant bacteria in the environment and reduced the effects of antibiotics.[40].

At present, the emergence of resistant strains is unavoidable and is considered to be only a matter of time, and resistant strains will emerge months to years after antibiotics are used.[12]..The resistance of sulfa drugs became known in the 1930s, and penicillin discovered in 1928 was found by the developers of penicillin in 1940, before it was used in earnest. Have been discovered[14]..In addition to sulfa drugs and penicillin, for example, streptomycin was discovered in 1944, and resistant bacteria were discovered the year after it was discovered.Vancomycin is an exception, with the emergence of resistant strains in 30, approximately 1987 years after introduction.It is considered that the limited use of vancomycin was behind the delay in the development of resistance.This is due to the availability of better antibiotics than vancomycin during the 1950s and 1960s.[12].

Almost no new antibiotics are discovered since the 1970s[25]. For example,GlaxoSmithKline,AstraZenecaConducted new drug development research by large-scale screening, but has not reached the practical use of the target antibiotic[26]..On the other hand, with the emergence of resistant bacteria, existing antibiotics lose their effectiveness.Therefore, new antibacterial agents will be developed by modifying existing antibiotics to increase their activity or reduce their toxicity to humans.However, as bacteria acquire resistance to modified antibiotics, "cat and mouse" continues between humans and bacteria.[25]..In recent years, of the ocean and humansMicro biomeAttempts have also been made to search for antibiotics from environments other than soil, such as[26].

With the emergence of resistant bacteria to antibiotics and the decrease in newly developed antibiotics, alternatives to antibiotics are being studied.Alternatives in this context are compounds that do not control the bacterium with compounds such as antibacterial agents, but are different from compounds that target the body of the host infected by the bacterium or conventional antibiotics that target the bacterium. To say.Targeting bacteria as a typical exampleantibodyDefined as a microorganism that brings health benefits to the hostProbiotics,PhageHas the function of dissolving bacteriaRaishinAnd the phage itself,Innate immune systemAn immunostimulant that activates, to prevent infectionvaccineAnd so on[41].

Sort

There are two classifications of antibiotics, one by chemical structure and the other by action.[1]..The former cannot classify new antibiotics, and the latter may not be able to classify antibiotics whose mechanism of action has not been rigorously investigated.Therefore, the classification that considers both is ideal.[42].

In the classification from the chemical structure,β-lactam,Aminoglycoside,Macrolide system,Tetracycline,peptidesystem,Nucleic acidsystem,Polyene systemIt is roughly divided into, but more detailedpenicillinsystem,Cephem system,MonobactamSometimes a system is added[1].

Classification from action, antibacterial, antiMold(Fungus) Sex, antitumor, etc.When the purpose is emphasized, it is classified into medical use, animal use, agricultural use, etc.It may be divided into a wide range and a narrow range from the working area.[1].Mechanism of actionTherefore, there are also names such as cell wall action.[1].

Antibiotics used as antibacterial drugs

BacteriaAs an example of the classification of antibacterial agents according to the mechanism of action against, there are three major categories: cell wall synthesis inhibitor, protein synthesis inhibitor, and nucleic acid synthesis inhibitor.[43]..In addition, folic acid metabolism inhibitors may be added to classify into four categories.[12].

Cell wall synthesis inhibitor

Beta-lactam antibiotics, which are classified as cell wall synthesis inhibitorsFosfomycin,VancomycinThere is.

Cell wall synthetic pathway

Most bacteriaCell membraneOutside ofCell wallAlthough it has a structure called[Note 3], Animal cells do not have this.Bacteria are generallyGram stainIt is classified into Gram-positive bacteria and Gram-negative bacteria according to the stained image of, and both are distinguished by the difference in cell wall structure, but both cell walls are commonly called peptidoglycan.High molecularAs a constituent component.Bacterial cells are high insideOsmotic pressurePeptidoglycan has the function of protecting bacteria from this osmotic pressure.Therefore, bacteria lacking peptidoglycan die because their cell membranes rupture.[17].

Bacterial cell walls, also called peptidoglycan, are twoAmino sugarAnd 10amino acidThe cell wall is constructed by assembling the Murrain monomer composed of bricks like a brick.The Murrain monomer is synthesized intracellularly and then transported extracellularly.Glycosyltransferase With an enzyme called (GT)Penicillin binding protein By the action of both enzymes called (PBP), the cells are cross-linked to the existing cell wall, and the synthesis of the cell wall is promoted.These two enzymes are not necessarily different enzymes,E. coliIn the case of, PBP doubles as two enzymes.Among cell wall synthesis inhibitors, β-lactams and vancomycin inhibit the action of PBP, while fosfomycin inhibits the synthesis of murain monomers in cells.[17].

β-lactam

Beta-lactam antibiotics are the most popular antibiotics, with 65% of the antibiotics prescribed in the United States belonging to this family.[46].. A beta-lactam antibiotic discovered for the first time in the world in the 1920sPenicillin produced by, etc., a type of mold in the 1940sIn addition to the cephem type that was first discovered in Japan, various similar compounds such as carbapenem type and monobactam type are known.[47].. Among β-lactamsCephem systemIs often prescribed in particular, and about half of β-lactam prescriptions are cephem antibiotics.[46].

The β-lactams exert their pharmacological effects by inhibiting the action of PBP. D-alanine-D-alanine plays an important role in cell wall synthesis because PBP recognizes D-alanine-D-alanine present in the molecule of the murain monomer and forms crosslinks to promote cell wall synthesis. ..penicillinSince β-lactam antibiotics represented by the above have a structure similar to this D-alanine-D-alanine, they bind to PBP, and PBP cannot bind to the murein monomer.As a result, the cross-linking of the cell wall becomes insufficient, and the bacteria rupture to death.This is the mechanism of action of β-lactams[17][43].

As the name implies, the β-lactam system has a structure called a β-lactam ring. Accompanying this in β-lactamsSide chainVarious antibacterial agents with different antibacterial spectra have been derived and developed by changing the structure of[17].

Glycopeptide system

A typical example of glycopeptide antibiotics was a type of actinomycete in soil in 1953. It is vancomycin found in.Others such as teicoplanin are included in this strain[48].. The β-lactams bind to PBP and inhibit cell wall synthesis, whereasVancomycinIs said to act by binding to D-alanine-D-alanine, which is a part of the murain monomer, and inhibiting the polymerization of the murain monomer by GT.It is sometimes called the "last resort" because of its large size, which makes it difficult to pass through the outer cell membrane and side effects, but it has a different mechanism of action from the β-lactam system.Methicillin-resistant Staphylococcus aureusUsed as a therapeutic agent against bacterial infections that are resistant to β-lactam antibiotics, such as[17][49].

Fosfomycin

Fosfomycin was discovered in 1969,Streptomyces fradiaeProduced by actinomycetes such asPhosphoenolpyruvate OfanalogIs.Unlike the above two lines of cell wall synthesis inhibitors,FosfomycinBecomes a part of Murrain MonomerN-Acetylmuramic acidInhibits the production of. Shows synergistic effect when used in combination with β-lactam[17][50].

Protein synthesis inhibitor

The information stored in the DNA of an organismTranscriptionBymConverted to mRNA翻 訳BeenproteinUsed for the synthesis of.RibosomeIs a place for protein synthesis, and in the case of bacteria, the 70S ribosome is composed of a combination of 30S subunit and 50S subunit.[43]..Bacterial ribosomes have a partially different structure from human ribosomes, and protein synthesis inhibitors act with high affinity for bacterial ribosomes.[17]..Protein synthesis inhibitors do not affect the human protein synthesis system,MitochondriaBecause it acts on the ribosome, it also damages human cells at some doses.Therefore, it is also said to have quantitative selective toxicity.This is in contrast to cell wall synthesis inhibitors, which are highly safe for humans and exhibit qualitative selective toxicity because they inhibit cell wall synthesis that is not present in animal cells.[51]..Protein synthesis inhibitors can be broadly classified into two types, one that targets the 30S subunit and the other that targets the 50S subunit, depending on the target of inhibition.The former includes aminoglycosides and tetracyclines, and the latter includes chloramphenicol and macrolides.[43].Amino glycoside(Aminoglycoside) in 1943Streptomyces griseusSeparated fromstreptomycinIt is an antibiotic represented by, and has a wide antibacterial spectrum against both Gram-positive and Gram-negative bacteria.[52]..On the other hand, the uptake of amino glycosides into cells requires aerobic respiration and is not effective against anaerobic bacteria.[53][54].Macrolide systemIs a large molecule with a structure called a macrocyclic lactone composed of 12-16 atoms.[55]Low toxicity[56]Shows excellent antibacterial activity against gram-positive bacteria such as staphylococci[57]..As a typical example, actinomycetes in 1952Found fromerythromycinEtc. are known[55][58]. tetracyclineThe system is also an antibiotic with an extremely wide antibacterial spectrum, and has four continuous cyclic structures as nuclei.In addition to tetracycline, the side chain of tetracycline was changed to improve lipophilicity.Doxycycline,MinocyclineIs known.Tetracycline antibiotics bind to ribosomes and inhibit protein synthesis by inhibiting the binding of aminoacyl-tRNA to ribosomes.[59]. ChloramphenicolIs an antibiotic with an extremely broad antibacterial spectrum.However, it is highly toxic, such as showing bone marrow toxicity, and is not often used for therapeutic purposes.[17][60].

Nucleic acid synthesis inhibitor

Nucleic acid synthesis inhibitors are classified into RNA synthesis inhibitors and DNA synthesis inhibitors, both of which exhibit quantitative selective toxicity.The former isRNA polymeraseInhibitmSuppresses the synthesis of[17].. Separated in 1957Nocardia spp.,It produces an antibiotic called ha.RifampicinIs an RNA polymerase inhibitor obtained by chemically modifying rifamycin.tuberculosisUsed as a first-line drug in the treatment of[61][62].

Antibiotics used as antifungal drugs

Polyene macrolide system TheErgosterolCharacteristic of fungal cell membranes calledSterolCombine with.This binding deprives the cell membrane of ergosterol, which inhibits its function and is toxic to fungi.[63][64]..A type of actinomycete as a typical exampleProduced byAmphotericin BIs known[65]Used to treat serious systemic fungal infections[63].

Another component of the fungal cell wall1,3-β-glucanA candine system that inhibits the synthesis of candy is known.Candice antibioticsMicafunginIs a type of fungus isolated from the soil in Iwaki City, Fukushima Prefecture, An antifungal drug obtained by modifying a precursor produced by F-11899, which is also used by fungi that are resistant to other antifungal drugs.[66][67].

Antibiotics used as antitumor drugs

MitomycinIs intracellularreductionIt is an antibiotic that has the function of cross-linking DNA when activated.The enzyme that activates mitomycin is distributed throughout the body, but reduction is suppressed in an oxygen-rich environment.Therefore, it is in a relatively hypoxic state.Solid cancerEspecially because it is selectively toxic toMitomycin CIs used as an anti-cancer drug[68][69].

It also has the effect of cutting DNASquamous epithelial cancer,Malignant lymphomaUsed to treatBleomycinIt is structurally characteristic by having two triple bond carbons separated by a double bond.EnediyneAre known as antibiotics with antitumor activity[70].

Other antibiotics

AvermectinWon the Nobel Prize in Physiology or MedicineSatoshi OmuraActinomycetesStreptomyces avermitilisAn antiparasitic antibiotic isolated from, which functions as an ion channel inhibitor in invertebrates.Modified thisIvermectinIs used to treat parasitosis in humans and animals[71][72].

Some antibiotics have been reported to have antiviral effects[73][74][75]..For example, in animal experimentsNeomycin TheHerpes simplex virusIt showed antiviral activity against viruses such as.This antiviral effectAkiko IwasakiTheir research groupTLR3ThroughinterferonThis is explained by the activation of the inducing gene.However, this result does not recommend the use of antibiotics such as neomycin to treat viral infections.[74].

Search and production of antibiotics

AntibioticsActinomyceteProduced using secondary metabolic pathways such asSecondary metaboliteIs[76][71]..Secondary metabolites are substances that are not essential for the survival of living organisms.amino acid,sugar,vitamin,Nucleic acid,protein,LipidEssential for survivalPrimary metaboliteBiosynthesized from[71][72]..Various useful substances have been discovered in the secondary metabolites of living organisms, including antibiotics used to treat infectious diseases.screeningIt has been searched by a method called.Screening refers to searching for substances having the desired physiological activity from a large number of compound libraries, and in particular, secondary microbial metabolites contain a wide variety of compounds and are still considered to be useful resources even today.[71].

Antibiotic biosynthesis

Secondary metabolites such as antibiotics are biosynthesized using transient metabolites and similar compounds as precursors.[71]..Examples include β-lactam antibiotics such as penicillin and cephalosporins.These substancesPenicillumWith some fungi contained in the genus etc.StreptomycesIt is synthesized by some bacteria contained in the genus, etc., but β-lactam antibiotics are synthesized via intermediates commonly called, regardless of the microorganisms that produce them.This isopenicillin N is a tripeptideIsopenicillin N synthaseIt is synthesized by modifying with, and this tripeptide is furtherα-Aminoadipic acid,Cysteine,ValineIt is composed of 3 amino acids.In addition, this tripeptide is a normalPeptide synthesisUnlike ribosomes, they are synthesized without the involvement of ribosomes.Nonribosomal peptideAlso called[77]..As described above, β-lactam antibiotics are biosynthesized using amino acids as precursors.Similarlystreptomycin TheAminoglycosideAlthough antibiotics are classified as, aminoglycoside antibiotics are primary metabolites.glucoseIs produced as a precursor.Macrolide TheAcetic acid,Propionic acidSuch asShort chain fatty acidsIs biosynthesized as a precursor.In addition, the secondary metabolic pathway uses not only precursors but also energy and coenzymes required for synthesis that can be obtained by primary metabolism.[11][72].

Search for antibiotics

Since Fleming's discovery of penicillin in 1928, tens of thousands of microbially-derived natural compounds, including antibiotics, have been discovered.[3], 60% of clinically used antibiotics are derived from actinomycetes.Actinomycetes are bacteria that grow like molds in the form of hyphae and generally inhabit the soil.It is said that 1 g of soil usually contains 1 million bacteria, 1,000 million actinomycetes, and 100 million molds, from which antibiotics are obtained.However, there are only a few antibiotics that satisfy the conditions such as low toxicity to the human body, sufficient effect on resistant bacteria, low price and stable supply, and among the discovered antibiotics, they are put into practical use. Is less than 10%[76].

The search for antibiotics in soil is carried out by the following method.First, the soil is collected.After suspending this in sterilized water, the suspended water is applied to the surface of the agar medium.After a few days, in a mediumcolonyWhen appears, isolate it and collect various microorganisms.Next, in order to investigate whether the collected microorganisms produce antibiotics, the collected microorganisms are cultured in a liquid medium to obtain a culture solution.If the collected microorganism is a microorganism that produces antibiotics, it is expected that the culture solution contains antibiotics, so the cells are removed by centrifugation, etc., and the culture solution from which the cells have been removed is used as the test sample. do.Next, in order to evaluate the effectiveness against bacteria, a gram-negative bacterium or a gram-positive bacterium is applied to an agar medium as a test bacterium, and a filter paper impregnated with a test sample is placed on the agar medium.If the cells are cultured overnight and an inhibition circle is formed around the filter paper, which means that the test bacteria are stunted, the originally collected microorganisms are considered to be antibiotic-producing bacteria and are produced by these microorganisms. Investigation of the chemical structure and mechanism of action of substances is carried out[76][78][79].

If it is confirmed that it is a new antibiotic structurally, safety tests are conducted by non-clinical studies and clinical studies, and if it is further examined and passed, it will be manufactured.Through these steps, it takes 10 to 15 years for an antibiotic to be approved and used.[76][80]..Furthermore, on average, one-sixteenth of the antibacterial drugs that have started clinical trials are said to be practical.[80]..Development of antibacterial drugs has a large risk such as cost for pharmaceutical companies, and major pharmaceutical companies are more expensive than development of antibacterial drugs.Lifestyle-related diseases,Chronic illnessThe focus is on the development of profitable therapeutic agents such as[3].

on the other hand,Genome sequenceAs a result of decoding, it was revealed that actinomycetes have biosynthetic genes of 20-30 types of secondary metabolites, of which 8% are dormant and secondary metabolites are produced. It is known that it is not produced or the production volume is extremely low.The dormant gene can be made manifest by devising the culture conditions, and can be utilized as a new genetic resource.Such a method is also called, and is expected as a new method for searching for antibiotic resources.[3][76][71].

Antibiotic production

Industrial production of antibiotics is achieved by fermentation.Most antibiotics are complex in structureAsymmetric centerIt is difficult to commercialize natural antibiotics by total chemical synthesis because of the large amount of antibiotics.For example, aminoglycosidesTeicoplaninAlthough a total synthesis method has been reported, it has not been put into practical use due to its high cost.However, quality control is also difficult for production by fermentation.This is because impurities differ depending on the type of strain used for fermentation and fermentation conditions vary, and some antibiotics are produced as a mixture of similar compounds.[81].

The production of many antibiotics is zymologically produced, and the method of production has changed little between the time immediately after World War II and the 60 years.[81]..Here, a method for producing β-lactam antibiotics is taken as an example.First, penicillin-producing bacteria are cultured and grown in flasks under conditions that do not produce antibiotics.Gradually increase the scale and grow, eventually changing the medium to one for antibiotic productionHalf cultureProduce antibiotics by[81][82]..The volume of the culture tank ranges from 20,000 to 60,000 gallons, and the culture takes 120 to 200 hours.During fermentation, in addition to oxygen, sugars such as glucose and sucrose are continuously supplied as a carbon source.Since penicillin is excreted in the culture medium, the culture medium is collected at the final stage of fermentation and is removed from the culture medium.Solvent extractionPurify penicillin with.ImpuresActivated carbonIs removed and finally crystallized as a potassium salt. As of the 1990s, penicillin production costs $ 10 to $ 20 per kg.75% of the penicillin produced is further modified and used as a semi-synthetic beta-lactam antibiotic[82].

Beta-lactam antibioticsCephalosporin CIs also produced by fermentation like penicillin.Cephalosporin C is produced by half-culture of fungi, but the energy source is replaced from sugar with fats and oils such as soybean oil and peanut oil at the stage of antibiotic production.This promotes the formation and promotes the production of cephalosporins by segmental spores.OtherMethionine,oxygen,nitrogenEtc. affect segmental sporulation and cephalosporin C production.However, most of the cephalosporin C is decomposed by chemical or enzymatic chemical methods.7-Aminocephalosporonic acidConverted to and used for the synthesis of other semi-synthetic antibiotics[82][83].

Also, not all antibiotics are produced by fermentation.Even with the same beta-lactam antibioticsCarbapenem systemAntibiotics were first obtained from actinomycetesThienamycinIs unstable, and in addition, intermediates useful for semisynthesis cannot be obtained by fermentation, so it is produced by total synthesis using inexpensive materials such as amino acids as raw materials.[81][84].

Medical use

Most of the antibiotics are used as antibacterial agents.How to administer antibacterial drugsClinical pharmacologyThe idea of ​​is applied.The administration of antibiotics for bacterial infections is clinically summarized, although antibiotics are different from chemotherapeutic agents.chemical treatmentIt is called.

In addition, polyene macrolide antibiotics are used to treat fungi.Also, for cancer treatmentMitomycin C,Bleomycin,Adriamycin,DoxorubicinAntibiotics such as are used.AlsoCyclosporine,Tacrolimus,EverolimusIs also an antibiotic,ImmunosuppressantAsCollagen disease,Autoimmune disease, Active in the field of transplantation medicine.

Treatment with antibiotics

If a symptom is suspected to be due to an infection and the pathogen that caused it is unclearEmpiric treatmentMay do[85]..In empirical therapy, broad-spectrum antibiotics are given based on symptoms without waiting for the results of culture tests, which can take several days to produce results.[86][85]..In order to strictly identify the causative agent of infection, it is necessary to carry out tests such as culture, but it may be possible to estimate the pathogen from the symptoms.for example,CellulitisSince it can be presumed that streptococci and staphylococci are the most likely pathogens, treatment with antibacterial agents can be started even if the culture does not give a positive result.[85]..On the other hand, if the pathogenic microorganism is known in advance or identified by a test, an antibiotic having a narrow antibacterial spectrum is administered.Identification of pathogens is important to reduce the cost and toxicity of antibiotic administration and to control the emergence of resistant strains.[85].

If the culture identifies the pathogen, thenDrug susceptibility testAnd test whether the pathogen can grow in the presence of certain antibacterial agents.Obtained in a drug susceptibility testMinimum inhibitory concentrationBased on the value of, it is determined whether the pathogen is sensitive, resistant, or intermediate to each drug.Sensitivity means that the infection can be treated with the amount of antibiotics normally given.Normally, this process makes it possible to narrow down the effective antibacterial agents.[85].

Antibiotics may be used prophylactically, but prophylactic administrationImmunosuppressive drugThose who are taking medication,cancerpatient,手術Limited to administration to people with a weakened immune system, such as patients who have suffered, especiallyHuman immunodeficiency virusIn infected peoplepneumoniaIs administered to prevent[86]..Administration of antibiotics in surgeryIncisionPrevent site infections.Prophylactic antibiotic administration plays an important role in oral surgery, followed by bloodstream infectionsInfective endocarditisTo prevent.again,NeutropeniaIt is also used to prevent infections inchemical treatmentPerformed for those who receive cancer treatment by[87][88][89]..However, after the problem of drug-resistant bacteria has grown, the effect of prophylactic administration may have decreased compared to before.[90].

Route of administration

Various antibioticsRoute of administrationhave.NormallyOral administrationIt is often done, but in the case ofDripOr may be given by injection[85]..Antibiotics may be given topically if the infected area is exposed, for example.ConjunctivitisIn case ofconjunctivaAgainsteye dropsAs acuteotitis externaIn the case of, it is administered as.again,Acne,CellulitisFor the treatment of skin diseases such asExternal medicineAntibiotics may be used as[91]..The advantage of topical administration is that the concentration of the antibiotic at the administration site is high and can be maintained for a long time.This can reduce systemic absorption and toxicity, reduce antibiotic doses and therefore reduce the risk of abuse.[92]..Topical administration of antibiotics to surgical wounds has been reported to reduce the risk of surgical wound infection.[93]..However, there are generally concerns about topical administration of antibiotics.Antibiotics can also be absorbed and transferred systemically, making it difficult to accurately regulate antibiotic doses.Also localHypersensitivity reactionAndContact dermatitisMay also occur[92].

Combination therapy

Simultaneous use of several antibiotics in the treatment of infectious diseases such as tuberculosisCombination therapyMay be done[94]..The combination therapy is performed for the purpose of expanding the antibacterial spectrum in empirical treatment, increasing the therapeutic effect by synergistic effect, and suppressing the emergence of resistant bacteria.[95]..In acute bacterial infections, a combination of multiple antibiotics that are more effective than a single agent is administered with the aim of synergistic effects in order to improve the therapeutic effect.[96][97],Methicillin-resistant Staphylococcus aureusIn the infection ofFusidic acidRifampicinTreatment is performed in combination with[96]..Amino glycosides or fluoroquinolones are combined with β-lactams when treating Gram-negative bacterial infections with combination therapy.[95]..In addition, the combination of antibiotics may be lower than that of single agent administration, which is called an antagonistic effect.[96]..In general, the combination of bacteriostatic and bactericidal antibiotics is antagonistic.[96][97]..However, the effectiveness of combination therapy may only be demonstrated under experimental conditions, and some have questioned the clinical efficacy of combination therapy against Gram-negative bacteria, for example.[95].

In addition to the combination of antibiotics and other antibiotics, antibiotics may be used with drugs that reduce resistance to antibiotics.For example, an enzyme that breaks down beta-lactam antibiotics.β-lactamaseBeta-lactam antibiotics are available for patients infected with bacteriaClavulanic acid,SulbactamMay be used in combination with[98].

Use for animals and plants

Antibiotics are used not only in human medicine, but also in animals and plants[99][100]..Many antibiotics are used for both humans and other animals, although some are used only for humans and some are used only for animals.Non-human animals to which antibiotics can be administeredmammalian,birds,Fishes,昆虫Etc. are exemplified.Some antibiotics, such as tetracyclines and streptomycin, are also used on fruit trees.[99][101].. According to 1997 statistics, while 5,460,000 kg of antibiotics were used in human medical applications in Europe, the amount used in animals reached 5,040,000 kg, and about 50% of the antibiotics used in animals worldwide. Presumed to be used for[100]. Also,US Food and Drug Administrationによると、2019年の一年間でアメリカ合衆国内において動物用に販売された、医療用にも使用される抗菌薬の量は6,189,260 kgに上り、その内67%をテトラサイクリン系抗生物質が占めていた。なお、動物に対する抗菌薬の使用量は2015年の9,702,943 kgが最大となっており、それと比べると36%減少している。また、動物の種別では牛と豚に対する抗菌薬の使用がそれぞれ2,529,281 kgと2,582,399 kgに及び、これは動物に対する抗菌薬の使用量のそれぞれ41%と42%を占めている[102].

Use on animals

As described above, when an antibacterial drug is used for humans, the administration of the antibacterial drug is basically intended for treatment.On the other hand, the situation is different when used for animals other than humans.Like dogs and cats among animalsPetWhen antibacterial agents are used, the usage policy is the same as for humans, and in principle, antibacterial agents are used for individual animals for the purpose of treating infection.Exceptionally, prophylactic administration may be given, but this is limited to certain conditions, such as after surgery.On the other hand, in the case of animals raised for the purpose of meat, even if some individuals in the group show symptoms and the majority of individuals are asymptomatic, antibacterial agents may be administered to the entire group through food or water. be.Such population-based antibiotics are rarely used on humans and are only used on specific individuals, such as individuals with close contact.[99].

Most controversial is aimed at promoting growthEconomic animalLong-term use of low-dose antibiotics against.It is not aimed at treating animals, but antibiotics are used for economic reasons.The use of antibiotics in livestock began in the 1950s, and the administration of low-dose antibiotics to livestock by farmers in the United States has been used to significantly accelerate the weight gain of livestock.Antibacterial agents classified as antibiotics used for fattening purposes include, for example, penicillin, oxytetracycline, erythromycin, etc.Spiramycin,TylosinAnd so on[103]..Even low doses of antibiotics to laboratory animal mice showed weight gain.Antibiotic administration and weight gain were also associated with 6-month-old human infants[104]..Reproducibility has been shown that low doses of antibiotics are effective in promoting growth, but the mechanism is unclear.It is also known that such effects do not occur in a hygienic environment.There is a theory that it is due to affecting the intestinal microflora, but whyMinimum inhibitory concentrationIt is unclear that less than a few antibiotics are effective.for that reason,Immune systemInCytokineA mechanism has also been proposed that suppresses the release of animals and, as a result, protects animals from loss of appetite.[105][106].

Prolonged use of low-dose antibiotics is prone to develop resistant strains, which can be transmitted to humans not only between animals but also through the diet and environment.[99]..For example, an antibiotic that has a structure similar to vancomycin and is effective against Gram-positive bacteria.AvoparcinIs used to promote the growth of poultry and pigs, but on farms that use avoparcin.Vancomycin resistant enterococciIs more likely to be detected.Vancomycin-resistant enterococci have been detected in livestock in the United Kingdom, Germany, and Denmark, and it is believed that these resistant bacteria spread rapidly in medical facilities in Europe and the United States.[107]..In addition, there is no economic benefit from the use of antimicrobials, or even if there is, it is small compared to the emergence of resistance.[99]..On the other hand, Europe has completely banned the use of antibacterial drugs for the purpose of promoting growth since 2006.[108]..A study in Denmark did not reduce the detection rate of vancomycin-resistant enterococci only by banning the use of avoparcin to promote livestock growth, but also banned the use of macrolide antibiotics. The detection rate decreased.This is a vancomycin resistance genevanAAnd macrolide resistance genesermB chainExplained by propagating[107].

Use for plants

The use of antibiotics in livestock began in the 1950s, but also for plants penicillin, streptomycin,Chlortetracycline, Chloramphenicol,OxytetracyclineSince the late 1940s, it has been investigated whether such substances can be used to protect plants from diseases.However, low doses are ineffective, and high doses cause phytotoxicity.[Note 4]In fact, streptomycin and oxytetracycline have only been used for certain diseases because they are more expensive than other control methods.[101]..When used on plants, it is used by dissolving it in water and spraying it.Due to cost issues, it is only actually used for plants whose costs are easy to recover, such as expensive fruit trees and vegetables and foliage plants.[110]..In the United States, the amount of antibiotics used for plants is said to be less than 0.1% of the amount of antibiotics used in the United States.[111]..Streptomycin is the main antibiotic used to control plant diseases and is found in apples and pears.Erwinia amylovcauseInfects the petals and fruits of apples and pearsPseudomonas syringae, Tomatoes, etc.Used against pathogens such as.Oxytetracycline is used for spot bacterial diseases such as peaches.[101]..Besides, in Japan, it is a rice disease caused by mold.Rice blastTo controlBlasticidin S,KasugamycinAntibiotics such as are used[112][113].

Also of the plantrootAnd microorganisms may have a symbiotic relationship, and in particular, the place where fungi and plant roots interact is sometimes called.Some microorganisms in the rhizosphere, such as actinomycetes, produce antibiotics, which are also thought to suppress the growth of harmful microorganisms to plants.[114].

Tolerance and abuse

Drug resistance

In bacteriology, the ineffectiveness of antibacterial drugs is called resistance, and resistant bacteria are called resistant bacteria. Resistant bacteria have been reported for all antibiotics used as of 2009, as well as for synthetic antibacterial agents.[17]..For example, in the 1940s, virtually all Gram-positive bacteria were sensitive to penicillin.[115]Will be inspected in the hospital by 1991Staphylococcus aureus38% became resistant to methicillin, a beta-lactam antibiotic that is more potent than penicillin[115][116].

Resistance acquisition mechanism

Bacteria's resistance to antibiotics can be either inherent in the bacterium or newly acquired.As an example of the formerPseudomonas aeruginosaHowever, due to the low permeability of the outer cell membrane, there is spontaneous resistance to many antibiotics.As a mechanism related to the latter resistance acquisition,Plasmid,TransposonIn addition to the uptake of foreign genes such asChromosomeMay be caused by the above mutation[12].

Incorporation of foreign genesHorizontal gene transferAlso called bacterial進化It plays an important role in the transmission of resistance genes.Antibiotics are derived from microorganisms that exist in the environment such as soil, but microorganisms that produce antibiotics are naturally resistant to the antibiotics.[117][40]..EcologicalnicheMicroorganisms that share the same have resistance genes to the antibiotic, and such genes are likely to be the source of resistance genes for pathogens detected in the medical field.[117]..In modern times, the soil-like environment is considered to be the major source of resistance genes in hospitals, humans and animals.Micro biomeIt is called a set of resistance genes in the environment including[40].

When resistance is acquired by mutation, cells with gene mutations that affect the activity of antibiotics emerge from the susceptible bacterial population, and the cells survive the antibiotic.Surviving cells are in the presence of antibioticsSelective pressurePriority is given to killing more susceptible bacteria, but resistance genes are generally costly and cannot be maintained in the absence of antibiotics.[117].

Tolerance mechanism

The mechanism of drug resistance is large: (1) prevention of accumulation of antibacterial agents by reducing uptake and promotion of excretion of antibacterial agents, (2) inactivation by decomposition or modification of antibacterial agents, (3) mutation or modification of target molecules of antibacterial agents. Classified as quantitative ineffectiveness of antimicrobials due to decreased affinity or overproduction[12][43].

As an example of the resistance mechanism by preventing the accumulation of antibacterial agents by reducing the uptake and excretion of antibacterial agentsPseudomonas aeruginosaHas natural resistance.All antibiotics exert their functions by passing through the outer membrane of bacteria and accumulating in the cells, but the outer membrane of Pseudomonas aeruginosa has low permeability of antibiotics, and antibiotics are generally difficult to work.It is also resistant to excretion of β-lactam antibiotics and quinolone antibacterial agents that have permeated into cells.[12][118].

Inactivation by degradation or modification of antimicrobial agents is a major mechanism of resistance to natural antibiotics such as beta-lactams.As a typical exampleβ-lactamaseThe mechanism of resistance to β-lactam antibiotics is known, and β-lactamase inhibits the binding of PBP to β-lactam antibiotics such as penicillin by hydrolyzing the beta-lactam ring structure, and is resistant to bacteria. Bring[12]..Hundreds of lactamase have been discovered so far, and are generally classified into four classes, A, B, C, and D.[17][43][119].. EspeciallyNew Delhi Metallo β-lactamase-1 Unlike other lactamases, β-lactamase called (NDM-1) is shared not only by a specific bacterial species but also by a large number of bacterial species, because the plasmid having the NDM-1 gene also has resistance genes of other strains. Bacteria that carry the plasmid become multidrug resistant and can easily spread in the environment because they can be transmitted to Escherichia coli, which causes diarrhea in children, and are recognized as a global health threat.[120][121].

Unlike antibiotics derived from natural products, no enzymes have been found that degrade or modify synthetic antibacterial agents such as sulfa drugs and quinolones.Resistance to such antibacterial agents is acquired by mutation or modification of the target molecule of the antibacterial agent to reduce affinity and quantitative ineffectiveness of the antibacterial agent by overproduction.[12]..For example, resistance to quinolone antibioticsDNA gyrase,DNA topoisomeraseEnzymes likegeneCaused by mutation in[43]..Resistance to natural product-derived antibiotics as well as synthetic antibacterial agents may be acquired by a similar mechanism.for exampletetracycline The16S ribosomal RNAIt is an antibiotic that inhibits protein synthesis by binding toHelicobacter pyloriHas been reported to acquire resistance by mutation of the 16S ribosomal RNA gene.[119].

Multidrug resistant bacteria

In recent yearsMethicillin-resistant Staphylococcus aureus,Multidrug-resistant tuberculosisBacteria that are resistant to multiple antibacterial agents have emerged.Resistance to multiple antibacterial drugs is called multidrug-resistant (MDR), and bacteria with multidrug resistance are called multidrug-resistant (MDR).Multidrug resistant bacteriaCalled.In addition, bacteria that are more resistant than multidrug-resistant bacteria are called extremely drug-resistant (XDR) bacteria, and bacteria that are resistant to all antibiotics are called pandrug-resistant (PDR) bacteria. Called a threat to public health[122][123]. For example,Center for Disease Control and PreventionEstimates that more than 23,000 people die annually in the United States from infections with multidrug-resistant bacteria[117].Mycobacterium tuberculosisMultidrug-resistant strains have emerged in many bacteria, including the above, and microorganisms with increased morbidity and mortality due to resistance to therapeutic antibiotics are sometimes called superbugs.[14]..Methicillin-resistant Staphylococcus aureus or a group of bacterial species called ESKAPE for the acronym (,Staphylococcus aureus,Klebsiella pneumoniae,,Pseudomonas aeruginosa,andEnterobacter) Is included in this, and it is regarded as a problem as a nosocomial infection-causing bacterium showing multidrug resistance.[121][124].

Post-antibiotic era and new drug development

Antibiotics have saved many lives, but the emergence of resistant bacteria has led to cases where existing antibiotics do not work, as mentioned above, and WHO is unable to treat infectious diseases with antibiotics in the "post-antibiotic era." I'm worried about the arrival of[125][126]..Therefore, it is expected that the development of new drugs that are effective against resistant bacteria will continue to be necessary in the future.[41]..Ocean and humanMicro biomeAttempts have been made to search for antibiotics from environments other than soil, such as[26], Others are expected as a new method for searching for antibiotic resources[3][76][71]..For example, in a study published in 2014,Human microbiomeObtained fromMetagenomicsBy exploringLactocillinSucceeded in isolating an unknown antibiotic called[127].. on the other hand,antibodyFormulation,Probiotics,Phage therapyThe development of alternative formulations that do not depend on antibiotics is also underway.[41].

As of 2020, SMEs play a central role in research on new drugs for these bacterial infectious diseases, and a review published in 2020.[128]Of the 314 businesses analyzed in, SMEs accounted for 81%.This review classifies the development projects for new antibiotics and antibiotic alternatives as follows.The first category is for direct action on bacterial cells, including classical antibiotics, to which 1 (187%) businesses belong. 46 businessesPhageIt is related to and acts directly on bacteria.The next category uses anti-pathogenic agents, which also applies to 33 businesses.For example, it is a mechanism that regulates gene expression according to the bacterial density.Quorum sensingThis includes drugs that inhibit the disease. 29 businessesantibodyIt is related to the toxin neutralizing antibody and the like. 27 businessesvaccine32 businesses are fortifying other drugs, typically other antibiotics, such as beta-lactamase inhibitors. 21 businessesMicrobiotaThe purpose is to regulate the intestinal microbial flora.ProbioticsIs applicable to this,Stool microbial transplantbyClostridium difficileTreatment of infectious diseases is being tested.In addition, diversion of immunostimulants and existing drugs,NanoparticlesDevelopment of pharmaceutical products using[128].

Phage therapy

Discovered in the 1910sPhage, Or a virus called bacteriophage, infects bacteria and kills them.Phage therapy is a method of using these phages to kill pathogenic bacteria.[125]..Although the potential for treating bacterial infectious diseases of phage was recognized around the 1930s and 1940s,Western countriesThen it was replaced by the antibiotics discovered at that time, and after that, the former Soviet Union etc.Eastern countriesResearch and practical use have advanced only in.However, in recent years, more than 60 years have passed, the emergence of pathogenic bacteria resistant to antibiotics has brought them into the limelight again.[129]..Because phages are specific for bacterial species, individual phage therapies target only specific bacterial species.Many research projectsPseudomonas aeruginosa,Staphylococcus aureusIs targeted, butClostridium difficileTreatments targeting other bacterial species, such as, or multiple bacterial species, are also under development.[128].

footnote

[How to use footnotes]

注 釈

  1. ^ Waksman defined the noun antibiotic in response to the question of the Editor-in-Chief of Biological Abstracts, but the year is ambiguous, 1941.[11]And in 1942[12]May be[13]..There is also a document that it was proposed in 1945.[9]..Also, antibiotic as an adjective form of antibiotic was used before Waksman used antibiotic as a noun.[13].
  2. ^ However, DomagkNaziDeclined the award once under the pressure of[35].
  3. ^ The cell wall exists in cells other than animal cells, that is, plant, fungal, and bacterial cells, but the components constituting the cell wall are different from each other.For plantscellulose,Hemicellulose,PectinBut for fungiKitchenBut bacteria contain peptidoglycan[44].. vice versaMycoplasmaThere are also bacteria that do not have a cell wall like[45].
  4. ^ For example, Blasticidin S produces pale yellow spots called drug spots on rice at high concentrations.[109].

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