The Aminoglycoside Drugs
Antibiotics composed of one or more amino sugars and an aminocyclitol (6-carbon) ring are referred to as aminoglycosides (figure 1). These complex compounds are exclusively the products of various species of soil actinomycetes in the genera Streptomyces and Micromonospora.
Fig1. The structure of an aminoglycoside: Streptomycin. Colored portions of the molecule are found in all members of this drug class.
Subgroups and Uses of Aminoglycosides
The aminoglycosides have a relatively broad antimicrobial spectrum because they inhibit protein synthesis by binding to one of the ribosomal subunits. They are especially useful in treating infections caused by aerobic gram-negative rods and certain gram-positive bacteria. Streptomycin is one of the oldest drugs but has gradually been replaced by newer forms with less mammalian toxicity. It is still the antibiotic of choice for treating bubonic plague and tularemia, and is considered an effective antituberculosis agent. Gentamicin is less toxic and is widely administered for infections caused by gram-negative rods (Escherichia, Pseudomonas, Salmonella, and Shigella). Two other aminoglycosides, tobramycin and amikacin, are also used for gram negative infections; tobramycin is especially useful for treating Pseudomonas infections in cystic fibrosis patients.
Tetracycline Antibiotics
The first antibiotic in this class was aureomycin. It was used to synthesize terramycin, tetracycline, and several semisynthetic derivatives, commonly known as the tetracyclines (figure 2.a). Their action of binding to ribosomes and blocking protein synthesis accounts for the broad-spectrum effects in the group.
Fig2. Structures of three antibiotics that act on prokaryotic ribosomes. (a) Tetracyclines. These are named for their regular group of four rings. The several types vary in structure and activity by substitution at the four R groups. (b) Chloramphenicol, a broad-spectrum drug with potentially serious side effects. (c) Erythromycin, an example of a macrolide drug. Its central feature is a large lactone ring to which two hexose sugars are attached.
Subgroups and Uses of Tetracyclines The scope of microorganisms inhibited by tetracyclines is very broad. It includes gram-positive and gram-negative rods and cocci, aerobic and anaerobic bacteria, mycoplasmas, rickettsias, and spirochetes. Tet racycline compounds such as doxycycline and minocycline are ad ministered orally to treat several sexually transmitted diseases, Rocky Mountain spotted fever, Lyme disease, typhus, Mycoplasma pneumonia, cholera, leptospirosis, acne, and even some protozoan infections. A newer derivative of minocycline—tigecycline—was developed to treat serious hospital skin and soft tissue infections in cases of drug resistance (Acinetobacter and MRSA). Although generic tetracycline is low in cost and easy to administer, its use can be limited by its side effects. In addition to gastrointestinal disruption due to changes in the normal microbiota and staining of the teeth, ingestion during pregnancy can interfere with fetal bone development (see table 1).
Table1. Major Adverse Toxic Reactions to Common Drug Groups
Chloramphenicol
Chloramphenicol is a potent broad-spectrum antibiotic with a unique nitrobenzene structure (figure 2b). Its primary effect on cells is to block peptide bond formation and protein synthesis. It is one type of antibiotic that is no longer derived from the natural source but is entirely synthesized through chemical processes. Al though this drug is as broad spectrum as the tetracyclines, it is so toxic to human cells that its uses are restricted. A small number of people undergoing long-term therapy with this drug incur irreversible damage to the bone marrow that usually results in a fatal form of aplastic anemia. Its administration is now limited to typhoid fever, brain abscesses, and rickettsial and chlamydial infections for which an alternative therapy is not available. Chloramphenicol should never be given in large doses repeatedly over a long time period, and the patient’s blood must be monitored during therapy.
Macrolides and Related Antibiotics
Erythromycin is a representative of antibiotics termed macrolides. Its structure consists of a large lactone ring with sugars attached (figure 2c). This drug has a moderate spectrum and fairly low toxicity. Its mode of action is to block protein synthesis by attaching to the 50S subunit of the ribosome. It is administered orally for Mycoplasma pneumonia, legionellosis, Chlamydia infections, pertussis, and diphtheria, and as a prophylactic drug prior to intestinal surgery. It also offers a useful substitute for dealing with penicillin-resistant streptococci and gonococci and for treating syphilis and acne. Newer semisynthetic macrolides include clarithromycin and azithromycin (Zithromax). Both drugs are useful for middle ear, respiratory, and skin infections and have been approved for Mycobacterium (MAC) infections in patients diagnosed with AIDS. Clarithromycin has additional applications in con trolling infections and gastric ulcers caused by Helicobacter pylori. Azithromycin is one of the most prescribed antibiotics in the world. It is used to treat respiratory, gastrointestinal, and sexually transmitted infections. One serious side effect it causes in some people is heart arrhythmias, which limits its use in sensitive people.
Clindamycin is a broad-spectrum antibiotic derived from lincomycin. The tendency of clindamycin to cause adverse reactions in the gastrointestinal tract limits its applications to (1) serious infections in the large intestine and abdomen due to anaerobic bacteria (Bacteroides and Clostridium), (2) infections with penicillin- resistant staphylococci, and (3) acne medications applied to the skin.
