Technically, the antibiotic era began with the discovery of penicillin by Sir Alexan- der Fleming in 1929. However, its development could occur only during World War II. By that time, an energetic soil scientist, Dr. Selman Waksman, had established a school of soil microbiology in New Jersey’s Rutgers University. Focusing on soil- borne aerobic actinomycetes, his group started a systematic program that lead to the discovery of streptomycin, an antibiotic credited with saving lives of millions of tuberculosis patients all over the world. Since then, his group at Rutgers as well as his students in various educational and industrial research laboratories went on to discover thousands of antibiotics, which include almost all the powerful drugs, such as tetracycline, erythromycin, chloramphenicol, amphotericin B, and vancomycin. Traditionally, the term “antibiotics” has been used for the antimicrobial agents derived from microorganisms. Since a number of antibiotics currently in use are actually synthetic, the term antibiotics has become synonymous with antimicrobial agents used for the treatment of infectious diseases.
CLASSIFICATION OF ANTIBIOTICS
From a structural perspective, antibiotics can be divided into several major categories.
Penicillin
Initially isolated from the mold Penicillium spp., penicillin is characterized by the presence of a β-lactam ring in the core structure (Fig. 3.1). Penicillin is, therefore, also called a β-lactam antibiotic. The β-lactam ring is sensitive to the enzyme β- lactamase, produced by a wide range of bacteria. In an attempt to develop a more effective drug, over time, the original penicillin (Penicillin G) has been repeatedly |
| Figure 3.1. Core structure of the penicillin molecule showing β–lactam ring |
modified. Newer penicillins include Penicillin V, Ampicillin, Methicillin, and Ticar- cillin. But the β-lactamase problem still persists. Penicillin is easily absorbed and apart from the anaphylactic shock noted in some sensitive individuals, its side effects are minimal. Greater research is needed to overcome its β-lactamase-related defi- ciencies. Its mechanisms of action involve blocking the reaction that leads to pep- tidoglycan cross links and the subsequent formation of the cell wall. Without the cell wall, bacteria have poor chance of survival.
Cephalosporins
Cephalosporins are produced by the mold Cephalosporium spp. They are also char- acterized by the presence of a β-lactam-like ring, but cephalosporins are relatively more resistant to classic β-lactamase, though they are sensitive to a different kind of β-lactamase. Advances in research on cephalosporins have led to the development of four generations of this antibiotic. They have a broad spectrum, and are often used in penicillin-sensitive individuals. Their mechanism of action is similar to that of penicillin.
Polypeptides or Glycopeptides
Polypeptides are a family of powerful antibiotics that include vancomycin and bacitracin. Vancomycin is produced by Streptomyces oreintalis, and bacitracin by Bacillus subtilis. Vancomycin is mostly active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is also considred a last resort drug in managing a number of infectious diseases. Its mechanism of action involves blocking the transpeptidation reaction by binding to D-alanine terminal sequence on the pentapeptide portion of the peptidoglycan and the eventual inhibition of cell wall biosynthesis.
Aminoglycosides
These are characterized by the presence of amino sugars linked by glycoside bonds (Fig. 3.2). They include streptomycin, neomycin, and gentamicin produced by Streptomyces griseus, S. fradiae, and Micromonospora purpurea, respectively. Newer agents include tobramycin and amikacin. For several decades, streptomycin was the only antibiotic effective against Mycobacterium tuberculosis, the principal causal
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Figure 3.2. Structure of streptomycin.
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Figure 3.3. Core structure
of tetracycline.
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agent of tuberculosis. Aminoglycosides are bactericidal and also effective against Gram-negative bacteria. Due to widespread resistance in Mycobacterium strains, the usefulness of streptomycin has been greatly, though not totally, diminished. The mechanism of action of this group of antibiotics involves blocking protein synthesis in bacterial cells by binding with the 30S subunit of the ribosomes. Aminoglycosides can be toxic, with severe side effects leading to kidney failure and hearing loss.
Tetracyclines
Original tetracycline was isolated from a strain of Streptomyces aureofaciens. It is characterized by the presence of four (tetra) interconnected rings (Fig. 3.3). Minor
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Figure 3.4. Structure of erythromycin.
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changes can be noted in different derivatives. For example, doxycycline has an extra OH group. The tetracycline group of antibiotics is bacteriostatic, hence an active immune system is essential in order to successfully treat an infection. These are broad spectrum antibiotics and useful in the treatment of infections by Gram-positive and Gram-negative bacteria, Rickettsia, Chlamydia, and Mycoplasma. Their mechanism of action is similar to that of aminoglycosides.
Macrolides
These are characterized by the presence a lactone ring linked to one or more sugars (Fig. 3.4). Erythromycin, produced by Streptomyces erythraeus, was the first com- monly prescribed macrolide antibiotic. It is a broad spectrum antibiotic effective against Gram-positive bacteria, some Gram-negative bacteria, Legionella, and Mycoplasma spp. Azithromycin and Clarithromycin are newer macrolide drugs which have surpassed erythromycin in their usage. Like tetracyclines, the macrolides are also bacteriostatic antibiotics. Their mechanism of action involves binding to the 23S ribosomal RNA of the 50S ribosome subunit to block protein synthesis.
Quinolones
Quinolones are synthetic antibiotics (Fig. 3.5). The best-known examples are ciprofloxacin, levofloxacin, and moxifloxacin. These are broad spectrum antibiotics and active against enteric bacteria, as well as against Haemophilus and Neisseria spp., and also show a varying degree of activity against Streptococcus pneumoniae and Pseudomonas aeruginosa. The mechanism of action includes inhibition of DNA replication by blocking bacterial topoisomerase. Since bacterial topoisomerases are different from mammalian topoisomerases, the mechanism of action is fairly selective.
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Figure 3.5. The core structure of ciprofloxacin.
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Figure 3.6.
Structure of amphotericin B (note the alternate double bonds at the bottom portion of the molecule).
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Polyenes
Produced by Streptomyces spp., polyenes are characterized by the presence of several alternate bonds in fused benzene rings (Fig. 3.6). Based on the number of alternate bonds, they are further classified as tetraene, pentaene, heptaene, and so on. The best known example is amphotericin B, which is a heptaene. Amphotericin B is often used for the treatment of invasive mycotic diseases, including invasive aspergillosis, zygomycosis, histoplasmosis, and coccidioidomycosis. Drug resistance to amphotericin B is not common. However, it is highly toxic to host and is not absorbed by the system. The mechanism of action involves forming a complex with ergosterol in fungal plasma membrane, which results in membrane leakage. Other well-known polyenes include nystatin and candicidin.
Metronidazole
Metronidazole is a nitroimidazole compound that is also known as flagyl. It is a synthetic antibiotic with a rather small molecule. It is effective against several anaerobic bacteria including Gardnerella vaginalis, Clostridium difficile, and a number of pathogenic protozoa, such as Giardia lamblia, Entamoeba histolytica,
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Figure 3.7.
Core structure of fluconazole.
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and Trichomonas vaginalis. It is not active against Gram-positive bacteria. The mechanism of action involves the initial reduction of metronidazole molecules by protein cofactors from microaerophilic bacteria (e.g., Bacteroides spp.). The reduced metronidazole molecule cuts DNA molecules in a random manner, thus causing death of the cells.
Azole Derivatives
Azoles are relatively a new class of antifungal agents. Their discovery and develop- ment has been primarily prompted by the toxicity of amphotericin B, the only thera- peutic agent available for the clinical management of systemic mycotic diseases. Currently they account for the largest number of antifungal drugs used for the man- agement of a wide range of mycotic diseases, from superficial to systemic infections. Azole-rings are typically characterized by an N-linked methyl group formed by added halogenated phenyls or similar groups (Fig. 3.7). Azoles are basically fungi- static. The mechanism of action involves blocking the synthesis of ergosterol, a vital component of the fungal cytoplasmic membrane. Several imidazoles interfere with cytochrome peroxidase and catalase activities, causing an increase in the level of hydrogen peroxide in the cells. Based on the number of nitrogen atoms in the ring, azoles can be divided into two groups, the imidazoles and triazoles. The imidazoles have two nitrogen atoms in the ring and include clotrimazole, miconazole, econ- azole, and ketoconazole. Of these, miconazole is mostly used in topical preparations for the management of cutaneous and mucocutaneous candidiasis. In contrast, the triazoles have three nitrogen atoms in the ring and include fluconazole, itraconazole, and terconazole. Fluconazole and itraconazole are used orally for the treatment of some of the systemic mycotic diseases.
Mebendazole
Mebendazole (methyl 5-benzoyl-2-benzimidazolecarbamate) is a synthetic agent with broad spectrum antihelminthic properties. The core structure consists of an imidazole ring linked to a benzene ring (Fig. 3.8). The mechanism of action involves
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| Figure 3.8. Core structure of mebendazole |
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Figure 3.9. Structure of ivermectin.
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the interruption of glucose uptake, resulting in the termination of ATP production and the subsequent death of the helminths. In addition or alternatively, mebendazole binds with the tubulins and interferes with the functioning of the microtubules by blocking the assembly of tubulin dimers into tubulin polymers. As a result, motility of the helminths is seriously impaired.
Avermectins (Ivermectin)
Avermectins, commercially marketed as ivermectin, are macrolide-like compounds (Fig. 3.9) produced by the bacterium Streptomyces avermitilis. In a classic sense it is an antibiotic that has antihelminthic properties and is widely used in agriculture to control nematode infections. In humans, it is primarily used against filarial para- sites. Its mechanism of action involves interfering with gamma-amino butyric acid (GABA) synapses in the nervous system in the helminths, resulting in their paralysis and removal from the host. Ivermectin is also known to interfere with reproduction in adult females. A single dose of ivermectin is considered enough to eliminate microfilaria for at least six months. In addition to the treatment of filariasis, ivermectin is effective against several other helminths including Ascaris, Trichuris, and Enterobius spp.
SUMMARY OF THE MECHANISMS OF ACTION
Most antimicrobial agents hit a specific target in the microbial cell. Examples of cellular targets and effective antibiotics are the following:
• Cell wall: Penicillins, cephalosporins, bacitracin, and vancomycin.
• Protein synthesis: Mostly work by blocking 30S and 50S subunits of the microbial 70S ribosome. Examples include tetracyclines, chloramphenicol, aminoglycosides, and erythromycin.
• DNA: There are several ways certain antibiotics can attack microbial DNA, either by directly damaging its integrity or by interfering with its replication. Examples include fluoroquinolones, rifampin, metronidazole, and sulfas.
• Cytoplasmic membrane: Certain antibiotics damage microbial cytoplasmic membranes. Examples include polyenes, polymyxin B, and azoles.
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