Antibiotics came into our lives almost 60 years ago as a result of the efforts of many scientists around the world. They are called the "miracle drugs" and they attack bacteria in many different ways. But microbes have various ways to survive, regroup and fight back.

DEFINITION

The word antibiotic derives from the greek words anti which means "against" and bios, which means "life". Usually the term antibiotic refers to a chemical compound that is used to kill or inhibit the growth of infectious organisms particularly bacteria and fungi.

In most cases the antibiotics are organic compounds which are produced by certain bacteria and molds and are toxic to other microorganisms. Apart from these natural antibiotics, there is a number of substances which are synthetic or semi-synthetic.

The major groups of antibiotics are penicillins, cephalosporins, aminoglycosides, tetracyclines, macrolides and sulphonamides.

HISTORY

Although for a contemporary person life without antibiotics seems rather inconceivable, people for thousands of years lived and died without having this valuable weapon against the "invisible" enemies — microbes.

It was the French chemist Luis Pasteur in the 19^th century who discovered that certain saprophytic bacteria can kill anthrax germs and that was the first time someone observed an antibiotic effect. In the following years other scientists, too, discovered substances that exhibited antimicrobial activity.

Rudolf von Emmerlich, in about 1900 isolated pyocynase. This substance although it could kill the germs of cholera and diphtheria, it could not cure the diseases. In 1909 a synthetic compound containing arsenic, salvarsan, was developed after the experiments of Paul Ehrlich. Salvarsan acted selectively against the bacteria that cause syphilis, and was used for treatment until penicillin was purified in the 1940s.

In the 1920s the Scottish bacteriologist Alexander Flemming was discovering lysozyme, a substance which is found in bodily secretions such as tears and sweat and has antimicrobial action mainly against harmless bacteria. Flemming continued his efforts and in 1928, he accidentally discovered penicillin. Penicillin is the product of the soil mold Penicillium notatum and proved to be effective against many types of disease causing bacteria. However, it was not until 1940 that the Australian Howard Florey and the Englishman Ernst Chain used penicillin on human beings and found commercial methods to produce it. During the second World War penicillin became widely available. In 1939 before penicillin was available to the public another antibiotic, tyrothricin, was used for the treatment of infectious diseases. Later in the 1940s Selman Waksman discovered streptomycin which is after penicillin, the most commonly administrated antibiotic and is effective against tuberculosis and several other diseases against which penicillin has no effect. The general use of antibiotics did not come until the 1950s.

ACTION OF ANTIBIOTICS

• Inhibition of cell wall synthesis

The bacterial cell is protected by a rigid structure, the cell wall, which determines its shape and prevents bursting as a result of the high osmotic pressure inside the cell.

A considerable number of antibiotics operates by inhibiting bacterial cell wall synthesis. These substances inhibit the synthesis of peptidoglycan, which is an important component of the bacterial cell wall or the synthesis of other cell wall components. The effect of the cell wall inhibitors is that the cell wall is weakened. The synthesis, however, of other cell materials is not affected and as the osmotic pressure of the cytoplasm increases, the cell wall collapses. Then the cell contents leak out and the cell dies.

An important characteristic of this kind of antibiotics is that they are active only during the cell’s growth. Moreover, such antibiotics are not effective against microorganisms that have no cell wall such as mycoplasmas, L-forms and protoplasts.

• Inhibition of the replication or transcription of genetic material.

The replication and the transcription of the nucleic acids (DNA and RNA), are vital functions. Synthesis of nucleic acids includes synthesis of nucleotides from intermediate molecules and polymerization of these nucleotides with the help of enzymes, according to the DNA template.

Antibiotics operate by inhibiting replication or transcription of the microbe’s genetic material. There are those, which inhibit the synthesis of nucleotides, and those, which inhibit the polymerization. Polymerization is inhibited either by inhibition of the template function of DNA or by inhibition of enzymes such as gyrase, DNA polymerase and RNA polymerase.

• Inhibition of protein synthesis

Proteins are composed of aminoacids. Each aminoacid attaches to a transfer RNA (t-RNA) before polymerization occurs, in a specific order determined by messenger-RNA. The polymerization of aminoacids takes place at the ribosomes.

According to their site of action, antibiotics can be divided to those which inhibit ribosomal functions and to those which inhibit extraribosomal factors.

• Inhibition of cell membrane functions

Bacteria, like eukaryotic cells are surrounded by a cell membrane. The cell membrane is the limit that distinguishes the internal of the bacterium from its surrounding, and it consists mainly of lipids and proteins according to the "mosaic" model.

Some antibiotics inhibit cell membrane functions by disorganizing its structure. This results in the loss of the cell’s components and eventually, the death of the bacterium. Other antibiotics act as carriers for specific ions, causing either abnormal accumulation or abnormal excretion of ions. These antibiotics are called ionophores.

Viruses

It is necessary to emphasize that although antibiotics inhibit the bacterial activity they generally have no effect on viruses.

DRUG-RESISTANCE

• Definition

Resistance is the ability of a bacterium to maintain its immunity to or resist the effects of a microorganism, toxin or drug.

• Ways of resistance

Drug-resistance can result from the inactivation of the antibiotic. An enzyme, which is produced by a resistance strain, can chemically alter the drug and thus, lead to inactivation. Such enzymes are the peptidases, the acetyl-transferases, the phosphoryl-transferases and the adenyl-transferases.

Resistance can also emerge from the modification of the target protein to which the antibiotic binds and forms a more or less stable complex. The resistant mutants either develop a target protein unable to bind the antibiotic or even if the antibiotic forms the complex, the target protein is still functional.

Antibiotics enter the microbial cell by passive diffusion or by active transport. In the case of passive diffusion it is difficult for the bacterium to become resistant without making changes that would be lethal. But when the antibiotic enters the cell with the help of a transport mechanism that involves a carrier protein, it needs only a small change in the structure of the protein to cause the impermeability of the membrane to a specific drug.

Increase in the production of the enzyme which is inhibited by the antibiotic can also result in drug-resistance.

CAUSES

The bacteria that infect an organism are not all the same, which means that some of them are more susceptible to antibiotics than others. The ones that survive pass the resistant gene to their progeny and increase in number. Those bacteria, which do not bear such gene, tend to disappear. It’s basic evolution.

Overprescription of antibiotics increases the evolutionary pressure put on the bacteria. Doctors as well as patients contribute to this problem. Patients usually want fast solution to any health problem and they believe that the use of antibiotics is the only treatment. For this reason they often put pressure on the physician and demand antibiotics for viral infections, like colds against which antibiotics are not effective. Moreover, doctors sometimes prescribe antibiotics without knowing whether a disease is caused by bacteria or not. What is even worse, is the trend to prescribe second-line and last resort antibiotics in place of first-line antibiotics, even when there is no reason to suspect resistance to older drugs. Thus, microbes are becoming resistant to more powerful drugs.

The following chart shows the rise in antibiotic sales in billions of dollars to drug stores and hospitals:

Patients contribute to the problem of drug-resistance in another way, too. When they do not complete their medication, they allow to some bacteria to survive and become resistant. Evolutionary pressure is again put on the bacteria and resistance is spread.

Use of antibiotics is even greater in poultry and livestock feed. Farmers use drugs to treat and prevent infections. But the main reason farmers use them is that they also make cows and chickens grow faster. Resistant bacteria emerge in animals the same way as in humans. Although high heat kills them, resistant variants spread from animals to people through raw or undercooked meat.

AIDS, an aging population and use of immune-suppressing drugs for chemotherapy and transplants are also responsible for the emergence of resistant strains. In these cases the weakened immunity system creates an environment where resistant variants emerge and spread quite easily.

World wide travel has offered the chance to various strains to exist in the same environment, exchange resistant genes and eventually, create new strains, resistant to a wider range of antibiotics.

RESULTS

In 1969, U.S. Surgeon General William Stewart testified before Congress that we "could close the book on infectious diseases". A few years later this proved to be quite untrue.

Indeed drug-resistance is a phenomenon that becomes more common as the years go by. Diseases such as tuberculosis, polio and diphtheria as well as Ebola fever in West Africa and dengue fever and dengue haemorrhagic fever in Latin America are reappearing threatening human lives. Strains of staphylococci are resistant to so many classes of antibiotics that the infections they cause are almost untreatable. Malaria is once again spreading in parts of Africa, the Middle-East, South- East Asia, and Latin America.

The number of antibiotics that do no longer work against strains of bacteria constantly increases. Vancomycin is currently the drug of the last resort. As it can be seen in the chart bellow microbes have become very powerful:

PRECAUTIONS

It is obvious that the more antibiotics are used the more pressure is put on the bacteria to evolve. Of course stopping the use of antibiotics is not the answer to the drug-resistance problem. Patients is necessary to take all the medication prescribed by the physician, even if they feel better before it ends. The patient should not follow medication prescribed for someone else and each case of infection must be examined separately. When the infection is caused by a virus doctors should not prescribe antibiotics even if the patient insists. The drugs used for the treatment of infectious diseases should target only a few bacterial types so as to minimize the chance of a multi-drug resistant strain to emerge.

Maybe the most important step towards preventing infections would be improvements in public health measures. More frequent hand washing by health-care workers, quick identification and isolation of patients with

drug-resistant infections, and improving sewage systems and water purity in developing nations are some of the improvements that need to be done.

Economic reinforcement of pharmaceutical companies to extend their research is also important in order for new, more effective drugs to be synthesized.

CONCLUSION

Antibiotics since they were discovered provided us with a powerful weapon against an invisible enemy that has always been threatening human lives. Today, the irresponsible use of antibiotics and the remarkable ability of bacteria to evolve have caused an unparalled rise of drug-resistant germs in recorded biological history. The end of miracle drugs may be closer than we thought and it is now more than ever necessary to act with responsibility.

1. Lancini G., Parentini F., Gallo G., 1995. Antibiotics A Multidisciplinary Approach, 85-100
2. Microsoft Corporation,1993-1996.Microsoft Encarta ΄97 Encyclopedia
3. Madigan M., Martinko J., Parker J. 1997.Biology of Microorganisms,307,422-427,878, 922-925
4. Newsweek. March 28, 1994, 38-44

Internet sources

1. http://micro.magnet.fsu.edu/micro/gallery/pharm/antibiotic/antibiotc.html
2. http://www.sciam.coom/explorations/072187bacteria/mirsky.html
3. http://www.ktv-i.com/news/nf09_18_97.html
4. http://www.mayohealth.org/mayo/9710/htm/antibiotic.htm
5. http://www.xoma.com/sci/BI_AnRes.html
6. http://www.fda.gov/fdac/features/795_antibio.html
7. http://falcon.cc.ukans.edu/~jbrown/antibiotic.html