Antibiotics 3482
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Antibiotics are substances that inhibit the growth of microorganisms (anti- metabolites ) or their replication (a bacteriostatic effect). They were traditionally obtained by extracting them from cultures of microbes. However, most drugs on the market today are semisynthetic derivatives of natural products. Sulfa drugs, discovered in the 1930s, were the first antimicrobial agents put into clinical use. Unfortunately, many bacteria are not susceptible to sulfonamides , and with the outbreak of World War II came the need for other more potent antibacterial agents. The serendipitous discovery of penicillin is, without a doubt, the most celebrated breakthrough in the history of antibiotics. In the late 1920s, while working in a London hospital, Alexander Fleming observed a mold overtaking a culture of staphylococcus bacteria he was growing in his laboratory. He extracted juices from the mold and, in 1929, reported that the extract, which he called penicillin, had antiseptic (anti-infectious) activity. The fungus was subsequently identified as Penicillium notatum (now called Penicillium chrysogenum ). It was not until the 1940s that penicillin was put into clinical use. Howard W. Florey, professor of pathology at Oxford's Sir William Dunn School of Pathology, and Ernst B. Chain are credited with culturing the fungus and producing the first significant quantities of penicillin for treating bacterial infections. In 1945 Fleming, Florey, and Chain received the Nobel Prize in physiology or medicine "for the discovery of penicillin and its curative effect in various infectious diseases."

A bottle of Amoxil, one brand name of semisynthetic penicillin amoxicillin.

Extracts from microorganisms are still an important source of antibiotics today. Clinically, antibiotics are described as possessing either broad- or narrow-spectrum activity. Bacteria are classified based on a staining technique developed by Danish microbiologist Hans Christian Gram. The bacterial cell walls of gram-positive bacteria stain blue when treated with either crystal violet or methylene blue, while gram-negative bacteria do not retain the stain and appear red. Broad-spectrum antibiotics are capable of inhibiting both gram-positive and gram-negative bacterial cultures. Grampositive bacteria have simpler cell walls than gram-negative strains and are susceptible to less toxic, narrow-spectrum antibiotics.

β -Lactam Antibiotics

A variety of penicillins have been produced by the fermentation of Penicillium chrysogenum in the presence of different nutrients. Penicillin G (benzylpenicillin; see Figure 1) predominates when the culture medium is rich in phenylacetic acid, whereas the incorporation of phenoxyacetic acid favors penicillin V (phenoxymethylpenicillin). Semisynthetic penicillins, such as ampicillin and amoxicillin, are prepared by replacing the aromatic side chain of biosynthetically derived penicillins with other chemical groups. All penicillins are β -lactam (see Figure 2) antibiotics and have the same mechanism of action: They inhibit bacterial cell wall biosynthesis .

Bacterial cell walls differ from mammalian cell walls and are therefore attractive targets for antibiotics. Bacterial cell walls contain β -lactam receptors , known as penicillin-binding proteins (PBPs). β -Lactam antibiotics

Figure 1. Penicillin G.
Figure 1. Penicillin G.

bind to the PBPs of bacterial cell walls and prevent their growth and repair. Widespread use of penicillin, however, has led to drug resistance . Because microorganisms multiply rapidly, strains of bacteria with enzymes capable of hydrolyzing β -lactam rings ( β -lactamases) have evolved. β -lactamases are capable of inactivating β -lactam antibiotics before they bind to receptors on cell walls. As a result, physicians sometimes prescribe β -lactamase inhibitors to patients on penicillin therapy to circumvent drug inactivation by bacterial enzymes.

Figure 2. The β-lactam ring.
Figure 2. The β -lactam ring.

The cephalosporins comprise another important class of broad-spectrum β -lactam antibiotics. Cephalosporins were originally isolated from cultures of Cephalosporium acremonium. Cephalexin (Keflex) is a semisynthetic cephalosporin frequently prescribed to treat ear and skin infections caused by staphylococci or streptococci.

Antibiotics That Inhibit Protein Synthesis

There are also a large number of antibiotics structurally unrelated to penicillins and cephalosporins. These compounds exert their antimicrobial activity by inhibiting protein biosynthesis. In 1947 chloramphenicol (see Figure 3) was isolated from cultures of Streptomyces venezuelae. It is a broad-spectrum bacteriostatic agent that interferes with protein synthesis by binding to bacterial ribosomes . The use of chloramphenicol in humans is limited because of the drug's toxicity. It inhibits liver enzymes and suppresses red blood cell formation.

Figure 3. Chloramphenicol.
Figure 3. Chloramphenicol.

Aminoglycosides are amino sugars with broad-spectrum antibiotic activity. Streptomycin , isolated from Streptomyces griseus , was the first aminoglycoside antibiotic discovered. Although streptomycin initially proved to be a potent agent against gram-negative bacteria, rapid microbial resistance to the drug has limited its use and today streptomycin is generally administered in combination with other antibiotics. Neomycin is a broad-spectrum aminoglycoside antibiotic isolated from Streptomyces fradiae. However, because of the adverse effects of neomycin on the kidneys and ear, its use in humans is restricted to topical applications, often in combination with other antibiotics or corticosteroids. Concerns over the potential risks associated with aminoglycoside therapy, chiefly nephrotoxicity (kidney disease) and ototoxicity (damage to the ear canal), have diminished their use.

In 1952 the broad-spectrum antibiotic erythromycin was isolated from cultures of Streptomyces erythreus (later renamed Saccharopolyspora erythraea ). The erythromycins are macrolide antibiotics that typically have a 12-, 14-, or 16-membered cyclic backbone which is a lactone (a cyclic ester ; see Figure 4).

Figure 4. 14-membered lactone.
Figure 4. 14-membered lactone.

Erythromycin A, the major fermentation component of S. erythraea , is a 14-membered ring macrolide that is used by medicinal chemists as the foundation for building semisynthetic derivatives of erythromycin antibiotics. (Macrolides inhibit bacteria by interfering with microbial protein biosynthesis.) Semisynthetic macrolides are popular with clinicians because they can be administered orally and have relatively low toxicity. They are often used to treat respiratory tract infections, and have been especially effective against conditions such as Legionnaires' disease and communityacquired pneumonia. Erythromycin therapy is often prescribed for individuals allergic to penicillin. One of the most widely used macrolide antibiotics

Figure 5. Tetracycline.
Figure 5. Tetracycline.

derived from erythromycin A is azithromycin (Zithromax). Resistance to macrolide antibiotics generally involves mutations of bacterial ribosomal RNA that prevent macrolide binding.

In the late 1940s and early 1950s a series of tetracycline antibiotics was isolated from cultures of streptomyces. All tetracyclines consist of four fused 6-membered rings (see Figure 5). Tetracyclines are broad-spectrum antibiotics that interfere with protein synthesis by binding to bacterial ribosomes. Unfortunately, the frequent use of tetracyclines to treat minor infections has led to resistance among previously susceptible strains of bacteria (pneumococci and staphylococci). Resistance to tetracyclines occurs when bacteria either develop proteins that prevent ribosomal binding by tetracyclines, or synthesize enzymes capable of inactivating tetracyclines.

Widespread use of antibiotics and rapid microbial evolution have led to highly resistant bacterial strains. Although most scientists no longer believe that a single drug will be developed to wipe out all infectious diseases, there is increasing demand for new antimicrobial agents. Currently, combined drug therapy appears to be the most effective means of circumventing microbial resistance to antibiotics.

SEE ALSO Fleming, Alexander ; Penicillin ; Sulfa Drugs .

Nanette M. Wachter


American Chemical Society (2000). The Pharmaceutical Century: Ten Decades of Drug Discovery. Washington, DC: ACS Publications.

Katzung, Bertram G. (1998). Basic & Clinical Pharmacology , 7th edition. Stamford, CT: Appleton & Lange.

Williams, David A., and Lemke, Thomas L. (2002). Foye's Principles of Medicinal Chemistry , 5th edition. Baltimore, MD: Lippincott Williams & Wilkins.


Internet Resources

"The Nobel Prize in Physiology or Medicine 1945." Nobel Foundation E-Museum. Available from .

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