Streptomyces and related manual labor

The relationship between fungi and infection have long attracted the interest of mankind, but the struggle between bacteria and germs, until the nineteenth century, it attracted the attention of scientists. Louis Pasteur and Robert Koch have noted that some Clostridium can inhibit the growth of Bacillus anthracis. However, such a discovery, in addition to the heap of paper so people sometimes your mind a move, on the development of antimicrobial agents failed to provide any substantive help.

Before and after the emergence of penicillin and sulfa, setting off a craze for antibacterial drugs for the scientists pointed out the direction of success, but also to stimulate their enthusiasm. In the middle of the last century, just a few decades, numerous scientists engaged in the study of bacteriology to go. Among them, Rutgers University (Rutgers University) of the 塞尔曼阿布拉 John Waxman (Selman Abraham Waksman, also a Nobel laureate), led by the laboratory, made the most brilliant achievement. In the four decades of his work, has discovered and synthesized by more than 20 kinds of antibiotics (or even the concept of antibiotics are his creation). Waxman's achievements not only quantity, but also a high degree. October 19, 1943, and his graduate student 艾伯特沙茨 (Albert Schatz) the success of gray Streptomyces (Streptomyces griseus), the extract of streptomycin.

Streptomycin is the gray synthesis and secretion of Streptomyces natural compounds. After following the penicillin, which is the second human to find secreted by microorganisms synthetic antibiotics. It appears to help human beings under control of tuberculosis and plague, but puts the study of antibiotics, the introduction of an inconvenience to blunt state.
Electron micrograph of Mycobacterium tuberculosis, slender slightly curved, reproduction time, it will be showing a branch-like hence the name. Looking and handsome, honest and simple and honest, once entered the body, from bones to hair follicles, from muscle to the brain, TB can infect almost any part of the body. And common bacterial cell wall peptidoglycan compared to the cell wall of Mycobacterium tuberculosis is very special, in which lipid substances particularly abundant. This thick layer of lipid "castles," although slightly inferior in mechanical strength and does not enable it to absorb a variety of nutrients - so slow-growing, and the nutritional demands are high - but for some can kill common bacteria The physical and chemical factors that have a strong resistance: in vitro Mycobacterium tuberculosis can survive in the Tanji in 6-8 months, in the air may remain infectious for nearly two weeks, or even 6% of the sulfuric acid or 4% sodium hydroxide solution and a half hours spent there activity; the human body, almost all of the defense system against bacteria, are helpless to it. TB is almost throughout the history of human civilization until the technological advances of today, each year about 800 million new cases continue to occur, at least 300 million people died of tuberculosis infection. So in human culture, "TB" once redolent with the death of a very perverted sense of beauty.

Mycobacterium tuberculosis is an impregnable fortress, so that the vast majority of the guys trying to discourage siege. However, penicillin, streptomycin did not choose a direct attack, as thick "wall" strategy, it found another ingenious way.

"Staring at the side of the ribosome would be orders (mRNA, also known as messenger RNA, a kind of qualitative information on the nuclear transfer and expression of nucleic acids), while operating lathes (tRNA, also known as transfer RNA, a kind of transfer of nucleic acid synthesis of raw materials), cautious and conscientious begin synthesis of proteins. " This passage vividly described the bacteria in vivo "Industrial Center" in full swing the labor scene: hundreds of thousands of ribosomes in order to meet the physiological requirements of bacteria, working round the clock forward.

Streptomycin is aimed at those within the impregnable fortress unsuspecting ribosomes. Once inside the cytoplasm of Mycobacterium tuberculosis, streptomycin molecule can be, and the small subunit ribosomal tightly intertwined, not only to prevent the ribosome near the lathe (tRNA), also would have been "on the machine" of the ribosome from the open bed truck driving, in addition, it also affects the ribosome correctly identify the "Order" (mRNA) content, resulting in processing of waste products out are useless, and sometimes the release of streptomycin has also blocked synthesis of ribosomal Good protein chain ... ... and so on and so forth. Anyway, as long as the bacterial ribosome has been streptomycin wraps, they do anything else, were all paralyzed. Human and bacterial ribosomes are structurally very different, so streptomycin can guarantee spoil when bacteria on the human ribosome Qiuhaowufan.

Streptomycin were not earth-shattering direct attacks on Mycobacterium tuberculosis lipid "wall," they quietly entered and fire a gun's not secretly Mojin bacteria attack the internal ribosome terrorist activities. Ribosomes were falling one after another, the bacteria lost the "Industrial Center" support, as a general strike broke out in the country, the rapid collapse, only a dead end.

More in-depth study found that streptomycin can also affect the membrane of protein synthesis. Cell membrane is an important function of places (see bacteria City Old things (on)), with a variety of functional proteins maintain the stability of the cell membrane, once the absence of these proteins, cell membrane stability is destroyed. In this way, not only the influx of more of streptomycin, the important functions within the bacterial cell nutrients will leak out and ultimately speed up the bacteria's death.

Streptomycin help mankind for the first time control of TB in this dangerous killer, after it was found that it can treat plague. Although the narrow range of streptomycin antibiotic, but the conquered people are scared of the big guys. Chemists were soon identified streptomycin structure: an N-methyl-glucosamine by streptavidin guanidine sugar and a combination of streptavidin molecules. People find what you want, and then developed a large number of the same pharmacological and streptomycin antibiotics, they all have a similar chemical structure, collectively known as the aminoglycosides (aminoglycosides).

From 1888, the United States University of Missouri campus and opened out a long 36 meters wide, 16 meters of the experimental field - Cimbault plots (sanborn field). Agriculture and scholars to study this piece of plots of land for planting crops in the ecosystem have occurred during the long-term variation. The study claimed to be the oldest one of several scientific studies. In the 100 years of time, derived from the observation Sambo plots to guide the United States continue to modify their land protection policy for the rational use of land has made outstanding contributions.

Duggar, Benjamin (Benjamin Duggar), Dr. once in this experimental field study of plant physiology. Early extensive research and experience, let him in plant physiology, bacterial and fungal physiology, have deep research. Into the American Cyanamid Company (Cyanamid Company), after he had been looking for enthusiasm for antimicrobial agents, but also into research and development of new drugs and going.

The advent of penicillin and streptomycin to solve a large number of infections. But then there are still a lot of infection, allow people to do nothing. In the penicillin inspired by Dr. Dagger sights he had studied the soil microflora. He firmly believed that, since penicillin can effectively control the infection, there must also be something else with the same Shen Xiao.

In 1945, from an experimental field of the soil samples from the Sambo, he from Streptomyces aureofaciens (Streptomyces aureofaciens) isolated a golden substance tested, he found that this substance can be confrontational, including Clostridium, Staphylococcus as well as a variety of pathogenic bacteria, including Streptococcus. Before this, he has completed as many as 3,500 times the sample screening test.

Inf.

Perhaps only because this substance golden yellow color, may be implied that he whom the tremendous efforts of Dr. Duggar, this isolated antibacterial drugs, named chlortetracycline (aureomycin). When chlortetracycline into clinical use, its broad antibacterial spectrum, low toxicity and high efficiency to prove that the drug is indeed just as precious as gold. Pharmaceutical researchers followed the study, Dr. Dagger ideas developed from the Streptomyces group of similar drugs. Through chemical analysis, found that the drugs have a similar four ring structure, so he used one of these drugs - Tetracycline - as their ethnic group's name.

Tetracycline molecular model

Mechanism of tetracycline and streptomycin are very similar, although the manner of tetracycline into the bacteria are more twists and turns, but once you enter the cell, are straight bacterial small subunit ribosomal away and completely destroy the function of ribosomal protein synthesis. In addition, tetracycline can also undermine the stability of the bacterial cell membrane, an important material for bacterial cell leakage died.

Streptomyces

If the advent of streptomycin proved Selman Abra • John • Waxman and his graduate student in drug research that has the talent, Dr. Dagger is successful, the value of this quality is the determination The most vivid interpretation. Under the influence of them all over the world-renowned researchers aware of unknown Streptomyces is likely to be a cornucopia of antibiotics, have squeezed into an already somewhat crowded field, it would be to the genus Streptomyces to find new antimicrobial agents.

One day in 1949, a Filipino scientist of some soil samples sent to his boss, Ai Li Lili (Eli Lilly). Lili's team very quickly from this red soil samples to extract Streptomyces, a substance in red. We all came to happy, because this has been confirmed that the red substance can also be anti-bacterial.

Since it is red, then called erythromycin bar.

We originally thought that erythromycin is also estimated to fight bacterial ribosomal small subunit idea. But let us rather unexpectedly, tetracycline, erythromycin and streptomycin, as well as the mechanism seem to have a great difference!

Pharmaceutical experts study pharmacological properties of erythromycin, when bacteria are very nervous, they claim, if a bully yet another small subunit ribosomal guy, they should quit! They must Stories behind Olympic in!

Soon, the results came out, pharmacology experts, announced: "Bacteria who ask you to rest assured! We represent the party on behalf of the government, with our party swear, erythromycin is not really aimed at the small subunit!" - Bacteria They breathe a sigh of relief, clutching the small ribosomal hands relaxed, twitter talking about the incident: "It's ah, with a total goal of Kill them staring at a whole, that is, migrant workers are also not stand up to, ah" - "Erythromycin targeted at a large ribosomal subunit! "... ...

Erythromycin can be a very smooth across the cell membrane, reversible combination of the bacterial large subunit of the ribosome, or to stop the activities of ribosomal protein synthesis, or simply destroy the overall structure of the ribosome. In any case, or by destroying the bacterial ribosome to achieve the purpose of killing bacteria.

And streptomycin and tetracycline, as after the discovery of erythromycin, (do not know if the same gang) people would not have developed a series of erythromycin-type drugs, such as clarithromycin, azithromycin and so on. The molecular structure of these drugs contain two sugar molecules and a large ring structure, such drugs would collectively known as macrolide antibiotics (Macrolide).

Streptomycin, tetracycline and macrolides appear, more and more scientists to participate in the study of Streptomyces and hope from its body out of the new antibacterial drugs, like the cow in humans, only one cow-like. In the conquest of bacteria on the road, although more and more crowded, but people hand in hand, tread Streptomyces and jump, farther spacious, farther joy, because the advent of erythromycin to prove that explore the antimicrobial drugs work has become a manual labor - this is actually a lot of people called scientists like to do, and do good work.

Perhaps the Streptomyces explorers who will then want to bring a language is also closed position, it is undeniable that the human conquest of the city's fight bacteria have become increasingly sophisticated, more mature. If the sulfonamides, penicillin is only human to inadvertently pick up the treasures, streptomycin, tetracycline and erythromycin was purely a result of our efforts to explore - from the story of Streptomyces, although also seen extraordinary creativity, but the More flooding is a stick poke in the end the determination of: Until today, there are people trying to come up with the body from Streptomyces new drugs.

Quinolone, an end and the start of

We can finally talk about a Streptomyces. To talk about malaria, rest.

Malaria is caused after Plasmodium infection of human disease. Records of the disease of mankind, at least 4000 years of history, and human malaria, there may be a more distant start. Europeans with the measles, smallpox and influenza in exchange for the cinchona from the Americas, after the ravages of malaria in the world has been convergence, but however, mankind is still suffering from the pain. The study of the cinchona stumbled lasted for nearly two centuries, still no one understand the principle of this drug. In 1820, the French chemists Pierre Joseph Pelletier (Pierre Joseph Pelletier) and Joseph Bulaimeika Ventou (Joseph Bienaimé Caventou) co-operation, and finally separated from the cinchona bark out malaria component quinine. Then spent another 100 years time, people only find out the chemical structure and characteristics of quinine, and then, a few Americans have found the method of synthetic quinine.

Quinine

This series of academic achievement and struggle against malaria in the face did not bring such a big difference. At that time the cost of industrial production is still high, had no choice but based on the production of quinine Cinchona tree planting. World War I, Germany could not import foreign goods, but to themselves to develop a substitute for quinine. Finally, in 1934, the German pharmaceutical company Bayer found a better efficacy of chloroquine - a kind of magic bullet instead of quinine to fight malaria.

Subsequently, many countries in the world have begun their own synthesis of chloroquine, the research work in this process have emerged a large number of by-product of an invalid. Blah-blah-blah-oxo-quinoline-carboxylic acid (7-chloro-1 ,4-dihydro-1-1ethyl-4oxoquinoline-3-carboxylicacid) is one of them.

Control of malaria drugs, usually rely on the impact of malaria parasite replication of genetic material, as well as nutrient intake. However, oxo-quinoline-carboxylic acid's role in this regard is not particularly prominent. For this common by-product, we do not have too much attention. Oxo-quinoline carboxylic acid is almost necessary that sank in numerous experiments in the log file. As has been widely used as a dye, like sulfa, when no one know that this sleeping drug has a wonderful performance, and soon, it will rise to a large class of promising anti-bacterial drugs, the study of antibiotics from Streptomyces dead end of the introduction of a new direction.

Bacterial cytoplasm is a crowded narrow space. In this space, floating around all the historical records of the bacteria, all the features of the material, nuclear transfer. Quality is a group of nuclear chromatin, the core material is repeated around the swing set of double-stranded circular DNA molecule.

Although the chemical structure of DNA complex, but its shape is relatively simple: 2 pentose phosphate skeleton of the middle, base with a special way, "writing" the genetic information, like a book, once to read the genetic information, open the Pentose skeleton, sentence by sentence to read on it. Bacterial DNA, stored, they are billions of years of history, a record of all the physiological functions. A micron level of Pseudomonas aeruginosa (Pseudomonas aeruginosa), whose DNA contains the number of base pairs can be one of more than 6,300,000, if fully extended, the length can be more than two millimeters. So it must be dense coil, a small cell in order to accommodate the very next. Pentose phosphate DNA backbone of the two equidistant wound to form a double helix structure, its appearance is like the diagram of the headphone cable wrapped with a local.

Please note that two headphone cable winding direction.
When the two headphone cable to continue to spiral, which headphones winding density of the line will be increased.

If readers have with such a headphone cable, they can try. In this state, the headphone cable or tend to revert to the previous state, or the right headphone wire the whole place will be a new wound. Please note that the new winding and the original wound in the opposite direction.

The event of a second winding, the original unstable headphone cable will be able to re-form a stable state. This is because for the first time generated when a certain winding increased "tension" would be released in the second winding. Two winding in the opposite direction, the release of the "tension," where the DNA of the wound more tightly.

Bacterial DNA, is that in this way a level to spiral wound to form a helix structure of DNA super (supercoil), will be 12 millimeters long DNA, down to micron range. And the headphone cable, like, super-spiral direction, and the pentose phosphate DNA backbone of rotation in the opposite direction, the situation prevailing in the biosphere, called the negative supercoils.

DNA, this compression method can maximize the use of the narrow cytoplasmic space of bacteria. However, if the extract genetic information from DNA - for example, in splitting the Pre-replication DNA - pentose skeleton must be opened, because the only way to read the DNA to carry genetic information.

However, it was impossible to DNA Expand to - DNA was too long - so just need to bacterial DNA, which for some information, it opens that particular paragraph. This is a best of both worlds approach, but the DNA of bacteria is a closed ring, as the figure we can see, when part of the DNA of the pentose skeleton is opened, the remaining part of the DNA of the "tense" degree would be more very. Thus, in order to release the DNA lysis when accompanied by a "tense", and the remaining super-helix structure of DNA must go further "anti-shally", otherwise the process of reading DNA can not continue, and even can not start.

In real life there is no constraint headphone cable to form a spiral can be four times rolling when you can loosen rejection to rejection go, but these are for the bacterial DNA is impossible. These processes must be in a series of special features of proteins - topoisomerase - under the control of a quiet and orderly manner. Bacteria can be divided into two types of four kinds of topoisomerase, the first class, two kinds of DNA-topoisomerase to help achieve the lysis; while super-helix structure of DNA to form even intensified, by the second category of DNA maneuver enzyme is responsible for.

DNA gyrase to help through the red chain green chain

The figure is a flowchart of DNA gyrase. This, DNA does not occur sharply turning, but also can form a closer negative super-helical structure.

Once this process a step in any problem of genetic information from DNA to read the process will be interrupted. In this way, bacteria not only can not copy the DNA to complete the division of reproductive, or even can not read the DNA information to guide the daily affairs of the city bacteria. Bacteria have lost the leadership of the central, only a dead end.

While lying on the document inside the heap-oxo-quinoline carboxylic acid, is the nature of the few features can damage the DNA gyrase is one of the substances. Once it into the bacterial cytoplasm, we can find a working DNA gyrase, when DNA gyrase has just cut the time it washed over the last card in between the DNA of the stump, forming DNA-gyrase - oxo-quinoline carboxylic acid complex. In this way the three cards is not an awkward together, looked at each other, stunned. Of course, DNA information, read the daily affairs, but also to a halt, the bacteria had to wait for death.

Then people will naturally do not know the secret. In the work of chloroquine, a synthetic drawing to a close, scientists have aimed at those "useless" by-product of the census screen, but this accidental discovery of this molecule to control poultry coccidiosis. It was an era of antibacterial drug discovery contest, the clues quickly attracted Qiaozhilaiche (Geodge lescher) of interest, and soon, he synthesis of oxo-quinoline carboxylic acid of similar drugs nalidixic acid (nalidixic acid). Fletcher found that nalidixic acid is not only an effective coccidiosis in poultry, but also control the effect of a number of other antimicrobial agents of Gram-negative bacteria is not very clear. In 1962, doctors try to use the drug treatment of urinary tract infections, and achieved good results.

Most of the drug from Streptomyces do not have a nalidixic acid shown efficacy, pharmacologists and biologists bacteria nalidixic acid and therefore full of curiosity. Subsequent research has opened a nalidixic acid and its similar drug, quinolone (Quinolone) damage DNA gyrase secret, for people to present a new concept of the antibacterial mechanism. Streptomyces rolling in before the rush to the body pharmacologists have found a new target, and soon a series of quinolone drugs to be available.

From 1962 to today, scientists have been engaged in improvement of the quinolones, and now has as many as five generations of quinolone antibacterial drugs into the first line, by virtue of their special anti-bacterial mechanism of quinolone drugs to potent, broad-spectrum antimicrobial drugs in the Chinese dominate. Based on the complexity of DNA physical features and the rapid development of modern pharmaceutical technology, many pharmacologists believe that quinolone antibacterial capacity and security features, there is a huge development space.

The emergence of quinolone-marked pharmaceutical science and technology bid farewell to the past, has entered a new era.

On the one hand, with the development of bacterial physiology and modern computer-aided pharmaceutical technologies, scientists are no longer satisfied with the numerous kinds of chemical substances in the blind test, according to the physiological characteristics of bacteria to design new drugs targeted exploration has already begun.
On the other hand, with the scientific and technological development, biologists have realized that this was originally part of the world of bacteria, almost every species, all have their own set of methods to combat bacteria. Bacteria dressed colorful this world, but the countless secret restraint bacteria are also hiding the meantime. As a result, scholars have put down the hands of the strength of live, temporarily let go of Streptomyces this poor guy will be a broader line of sight into the natural world.

In the struggle between humans and bacteria, a truly new era has finally arrived, this time we can go far, nobody could foresee.

From bacteria to walk out of the shadows, it seems only took less than a century. In fact, in order to achieve this leap, quietly prepared for thousands of years humans. In the last century, when man by his grill when igniting the flames of war, and efforts to combat bacteria suddenly get good returns, it all looks really like a coincidence. But a look at our own history, it all seems to be inevitable. In a city struggling to overcome the battle of bacteria, humans have finally found their own unique modes of struggle. A crowded planet, so that the most distant evolutionary tree separated two of the most adept in their respective ways closely fight in together. I believe mankind will come up with more and more effective means, but the struggle will never end, because the cruelty is the world's primary color.

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Reference

Basic & Clinical Pharmacology 9th Ed

Introductory clinical pharmacology 7th Ed

The Desk Encyclopedia of Microbiology edited by Moselio Schaechter

Dictionary of Biochemistry and Molecular Biology 2nd Ed By J. Stensen

Pharmacology People's Health Publishing House Editor Shi-Jie Yang

People's Health Publishing House of Medical Microbiology ZHOU Zheng-Ren editor

Including the various sites, including Wikipedia

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