20.1 The History of Chemotherapy

• While attempting to stain bacteria without staining the surrounding tissue, he speculated about some “magic bullet” that would selectively find and destroy pathogens but not harm the host. This idea provided the basis for both selective toxicity and chemotherapy, a term he coined.

• Antibiotic, a substance produced by microorganisms that in small amounts inhibits another microorganism.

  • More than half of our antibiotics are produced by species of Streptomyces, filamentous bacteria that commonly inhabit soil.

• The discovery and use of sulfa drugs made it clear that practical antimicrobials could be effective against systemic bacterial infections and resurrected interest in the earlier reports of penicillin

• Most antibiotics in use today were discovered by methods that required identifying and growing colonies of antibiotic producing organisms, mostly by screening soil samples.

  • To find an antibiotic that is produced by only one soil or sea microbe in 10 million is a daunting task.

20.2 Spectrum of Antimicrobial Activity

• These two cell types differ substantially in many ways, such as in the presence or absence of cell walls, the structure of their ribosomes, and details of their metabolism.

  • Viral infections are also particularly difficult to treat because the pathogen is within the human host’s cells and because the genetic information of the virus is directing the human cell to make viruses rather than to synthesize normal cellular materials

• Some drugs have a narrow spectrum of microbial activity, or range of different microbial types they affect.

• Antibiotics that affect a broad range of gram-positive or gram-negative bacteria are therefore called broad-spectrum antibiotics.

• A primary factor involved in the selective toxicity of antibacterial action lies in the lipopolysaccharide outer layer of gram-negative bacteria and the porins that form water-filled channels across this layer

  • The normal microbiota ordinarily compete with and check the growth of pathogens or other microbes.

20.3 The Action of Antimicrobial Drugs

• Antimicrobial drugs are either bactericidal (they kill microbes directly) or bacteriostatic (they prevent microbes from growing)

  • In bacteriostasis, the host’s own defenses, such as phagocytosis and antibody production, usually destroy the microorganisms.

• The cell wall of a bacterium consists of a macromolecular network called peptidoglycan.

• Penicillin, the first true antibiotic to be discovered and used if one does not also consider the sulfa drugs, is an example of an inhibitor of cell wall synthesis

  • Among the antibiotics that interfere with protein synthesis are chloramphenicol, erythromycin, streptomycin, and the tetracyclines

• Ionophores are antibiotics produced by several soil bacteria and fungi. They allow uncontrolled movement of cations across the plasma membrane.

• A number of antibiotics interfere with the processes of DNA replication and transcription in microorganisms.

20.4 Common Antimicrobial Drugs

• The term penicillin refers to a group of over 50 chemically related antibiotics

  • Penicillins prevent the cross-linking of the peptidoglycans, which interferes with the final stages of the synthesis of the cell walls, primarily of gram-positive bacteria

  • Penicillins extracted from cultures of Penicillium fungi are the so-called natural penicillins

• Procaine penicillin, a combination of the drugs procaine and penicillin G, is retained at detectable concentrations for up to 24 hours; the concentration peaks at about 4 hours.

• Penicillinases are enzymes produced by many bacteria, most notably Staphylococcus species, that cleave the β-lactam ring of the penicillin molecule

  • A large number of semisynthetic penicillins have been developed in attempts to overcome the disadvantages of natural penicillins

• The carbapenems are a class of β-lactam antibiotics that substitute a carbon atom for a sulfur atom and add a double bond to the penicillin nucleus.

• It’s a synthetic antibiotic that has only a single ring rather than the conventional β-lactam double ring, and it’s therefore known as a monobactam.

• Isoniazid (INH) is a very effective synthetic antimicrobial drug against Mycobacterium tuberculosis. The primary effect of INH is to inhibit the synthesis of mycolic acids, which are components of cell walls only of the mycobacteria.

• Chloramphenicol inhibits the formation of peptide bonds in the growing polypeptide chain by reacting with the 50S portion of the 70S prokaryotic ribosome.

• The oxazolidinones are another class of antibiotics developed in response to vancomycin resistance.

• The synthesis of bacterial plasma membranes requires the synthesis of fatty acids as building blocks.

• Researchers in search of an attractive target for new antibiotics have focused their attention on this metabolic step, which is distinct from the fatty acid biosynthesis in humans.

20.5 Tests to Guide Chemotherapy

• Several tests can be used to indicate which chemotherapeutic agent is most likely to combat a specific pathogen.

  • Tests are necessary only when susceptibility isn’t predictable or when antibiotic resistance problems develop.

• If the chemotherapeutic agent is effective, a zone of inhibition forms around the disk after a standardized incubation.

• For a drug with poor solubility, however, the zone of inhibition indicating that the microbe is sensitive will be smaller than for another drug that is more soluble and has diffused more widely.

• A more advanced diffusion method, the E test, enables a lab technician to estimate the minimal inhibitory concentration (MIC), the lowest antibiotic concentration that prevents visible bacterial growth.

• A broth dilution test is often useful in determining the MIC and the minimal bactericidal concentration (MBC) of an antimicrobial drug.

  • Dilution tests are often highly automated. The drugs are purchased already diluted into broth in wells formed in a plastic tray.

• After incubation, the turbidity may be read visually, although clinical laboratories with high workloads may read the trays with spectrophotometers that enter the data into a computer that provides a printout of the MIC

20.6 Resistance to Antimicrobial Drugs

• When first exposed to a new antibiotic, the susceptibility of microbes tends to be high, and their mortality rate is also high; there may be only a handful of survivors from a population of billions.

• Once acquired, however, the mutation is transmitted vertically by normal reproduction, and the progeny carry the genetic characteristics of the parent microbe.

• Destruction or inactivation by enzymes mainly affects antibiotics that are natural products, such as the penicillins and cephalosporins.

• Gram-negative bacteria are relatively more resistant to antibiotics because of the nature of their cell wall, which restricts absorption of many molecules to movements through openings called porins

  • Several antibiotics, especially those of the aminoglycoside, tetracycline, and macrolide groups, utilize a mode of action that inhibits protein synthesis at this site

• Antibiotic resistance is costly in many ways beyond those that are apparent in higher rates of disease and mortality.

  • Strains of bacteria that are resistant to antibiotics are particularly common among hospital workers, where antibiotics are in constant use.

20.7 Antibiotic Safety

• Administering almost any drug involves assessing risks against benefits; this is called the therapeutic index.

• Sometimes, the use of another drug can cause toxic effects that do not occur when the drug is taken alone.

20.8 Effects of Combination of Drugs

• Other combinations of drugs can show antagonism. For example, the simultaneous use of penicillin and tetracycline is often less effective than when either drug is used alone.

• The chemotherapeutic effect of two drugs given simultaneously is sometimes greater than the effect of either given alone which is called synergism.

20. 9 Future of Chemotherapeutic Agents

• As pathogens develop resistance to current chemotherapeutic agents, the need for new ones becomes more pressing.

• A truly new approach to controlling pathogens is to target their virulence factors rather than the microbe producing them.

  • The FDA requires that antibiotics be tested against exponentially growing pathogens.

• Microorganisms are not the only organisms that produce antimicrobial substances. Many birds, amphibians, plants, and mammals often produce antimicrobial peptides.

• Phage therapy has been used in Russia, Georgia, and Poland for more than 50 years.

  • Bacteriophages are viruses that can kill their host bacterial cells

  • Phages are specific for their host bacteria and may be useful to treat antibiotic-resistant infections.

• Finally, there is a special need for new antiviral drugs as well as antifungal and antiparasitic drugs effective against helminths and protozoans, because our arsenal in these categories is very limited