Antibiotic

I

Introduction

Antibiotic (Greek anti, “against”; bios, “life”), any chemical compound used to kill or inhibit the growth of infectious organisms, particularly bacteria and fungi. All antibiotics share the property of selective toxicity: they are more toxic to an invading organism than they are to an animal or human host.

Penicillin is the most well-known antibiotic and has been used to fight many infectious diseases, including syphilis, gonorrhoea, tetanus, and scarlet fever. Another antibiotic, streptomycin, is used to combat tuberculosis (TB). Originally the term antibiotic referred only to organic compounds, produced by bacteria or moulds, that are toxic to other micro-organisms. The term now includes synthetic and semi-synthetic as well as organic compounds. Antibiotic refers primarily to antibacterials but also includes anti-malarials and anti-protozoals. There are also a number of antivirals, but most viral infections cannot and should not be treated with an antibiotic.

II

History

Although the antibiotic mechanism was not scientifically understood until the 20th century, the principal of using organic compounds to fight infection has been known since ancient times. Crude plant extracts were used medicinally for centuries, and there is anecdotal evidence for the use of cheese moulds for topical treatment of infection. The first observation of what would now be called an antibiotic effect was made in the 19th century by the French chemist Louis Pasteur, who discovered that certain saprophytic bacteria can kill anthrax germs. In about 1900, German bacteriologist Rudolf von Emmerich isolated a substance called pyocyanase, which can kill the germs of cholera and diphtheria in a test tube. It did not prove useful, however, in curing disease.

In the first decade of the 20th century, the German doctor and chemist Paul Ehrlich began experimenting with the synthesis of organic compounds that would selectively attack an infecting organism without harming the host organism. His experiments led to the development, in 1909, of salvarsan, a synthetic compound containing arsenic, which exhibited selective action against spirochaetes, the bacteria that cause syphilis. Salvarsan remained the only effective treatment for syphilis until the purification of penicillin in the 1940s. In the 1920s British bacteriologist Alexander Fleming, who later discovered penicillin, found a substance called lysozyme in many bodily secretions, such as tears and sweat, and in certain other plant and animal substances. Lysozyme has strong antimicrobial activity, but mainly against harmless bacteria.

Penicillin, the archetype of antibiotics, is a derivative of the mould Penicillium notatum. Penicillin was discovered accidentally in 1928 by Fleming, who showed its effectiveness in laboratory cultures against many disease-producing bacteria, such as those that cause gonorrhoea and certain types of meningitis and septicaemia. This discovery marked the beginning of the development of antibacterial compounds produced by living organisms. Penicillin was first used on human beings by Howard Florey and Ernst Chain in 1940.

The first antibiotic to be used in the treatment of human disease was tyrothricin, isolated from certain soil bacteria by the American bacteriologist René Dubos in 1939. This substance is too toxic for general use, but it is employed in the external treatment of certain infections. Other antibiotics produced by a group of soil bacteria called actinomycetes have proved more successful. One of these, streptomycin, discovered in 1944 by the American biologist Selman Waksman and his associates, is effective against many diseases—including several against which penicillin is useless, especially tuberculosis.

Since antibiotics came into general use in the 1950s, they have transformed the patterns of disease and death. Many diseases that once headed the mortality tables—such as TB, pneumonia, and septicaemia—now hold lower positions, although TB has re-emerged in parts of the developed world. Surgical procedures, too, have been improved enormously, because lengthy and complex operations can now be carried out without a prohibitively high risk of infection.

Chemotherapy has also been used in the treatment or prevention of protozoal and fungal diseases, especially malaria, a major killer in developing nations. Slow progress is being made in the chemotherapeutic treatment of viral diseases. Drugs have been developed and used to treat shingles and chickenpox. There is also a continuing effort to find a cure for infection by the human immunodeficiency virus (HIV), which now occurs worldwide. There is, however, the growing problem of resistance to antibiotics, so that new ones are constantly being researched.

III

Classification

Antibiotics can be classified in several ways. The most common method classifies them according to their action against the infecting organism. Some antibiotics attack the cell wall; some disrupt the cell membrane; and the majority inhibit the synthesis of nucleic acids and proteins, the polymers that make up the bacterial cell. Another method classifies antibiotics according to which bacterial strains they affect: staphylococcus, streptococcus, or Escherichia coli, for example. Antibiotics are also classified based on chemical structure, as penicillins, cephalosporins, aminoglycosides, tetracyclines, macrolides, or sulphonamides, among others.

IV

Mechanisms of Action

Antibiotics can either selectively disrupt the cell membrane in some species of bacteria and fungi, or block bacterial protein synthesis. The antifungal amphotericin, for example, disrupts the chemical structure of the cell membrane in fungi, thereby preventing vital nutrients from being absorbed and allowing toxins into the fungal cell.

Most antibiotics operate by inhibiting the synthesis of various cell components. Some important and clinically useful drugs interfere with the synthesis of peptidoglycan, the most important component of the cell wall. These drugs include the β-lactam antibiotics, which are classified according to chemical structure into penicillins, cephalosporins, and carbapenems. All of the β-lactam antibiotics contain a ring as part of their chemical structure. The ring is critical in preventing peptides from attaching to side chains during cell-wall formation.

These compounds all inhibit peptidoglycan synthesis but do not interfere with the synthesis of the intracellular components. The continuing build-up of materials inside the cell exerts ever greater pressure on the membrane, which is no longer properly supported by peptidoglycan. The membrane gives way, the cell contents leak out, and the bacterium dies. These antibiotics are safe for use in humans because human cells do not have cell walls.

Many antibiotics operate by inhibiting the synthesis of various intracellular bacterial molecules, including DNA, RNA, ribosomes, and proteins. The synthetic sulphonamides are among the antibiotics that interfere with protein synthesis. Nucleic-acid synthesis can be stopped by antibiotics which inhibit the enzymes that assemble the polymers—for example, DNA polymerase or RNA polymerase. Examples of such antibiotics are actinomycin and rifampicin, the last one being particularly valuable in the treatment of TB.

The quinolone antibiotics inhibit synthesis of an enzyme responsible for the coiling and uncoiling of the chromosome, a process necessary for DNA replication and for transcription to messenger RNA. Some antibacterials affect messenger RNA by causing its genetic message to be garbled. When these faulty messages are translated, the protein products are non-functional. There are also other mechanisms: the tetracyclines compete with incoming transfer-RNA molecules; the aminoglycosides cause the genetic message to be misread and a defective protein to be produced; and chloramphenicol prevents the linking of amino acids to the growing protein.