CHAPTER 20 ANTIMICROBIAL DRUGS
Chemotherapeutic drugs (chemotherapy) combat disease in the body, whether it is
caused by a pathogenic microbe or something else (cancer)
An antimicrobial drug is a chemical that destroys pathogenic microbes with minimal
damage to the tissues of the host.
Antibiotic---this is specifically a chemical invented by one microbe to work against other
Synthetic---prepared in the laboratory, no microbe involved
Semisynthetic-----the original antibiotic is changed or modified in the lab
HISTORY OF CHEMOTHERAPY
1. Although chemotherapy with natural products such as herbs can be traced back far in
the history of man, Paul Ehrlich is given credit for the birth of modern chemotherapy.
He set out to create a treatment for syphilis that would cure the disease more reliably
and with less harm to the patient than existing treatments, which involved the use of
mercury. His discovery was Salvarsan, a modified form of arsenic. It was first called
Compound 606, because Ehrlich had tried 605 compounds before it which did not work.
2. In 1928, Alexander Fleming observed that a mold which had appeared as a
contaminant in a Petri dish of bacteria had prevented bacterial growth in the area
surrounding it. The mold was identified as Penicillium notatum. Fleming regarded his
discovery as a curiosity and made little effort to develop it.
3. In 1935, Domagk and Trefoil discovered and developed the antimicrobial properties of
a synthetic red dye called prontosil. Living cells change prontosil into sulfanilamide,
which is antimicrobial. At first, the sulfas were used as a powder to dust on wounds.
Later they were developed into systemic drugs, and derivatives are widely used today.
Since sulfas are synthetic, they are not true antibiotics.
4. In 1940, Florey and Chain worked with penicillin, the active compound in Fleming’s
discovery, and brought it to clinical trials. At that time, it was extremely difficult to
produce penicillin, but it showed promise. The work was moved to the US because of
the danger of bombing in England, and by the end of World War II penicillin was
becoming readily available. It worked like magic and was called the “wonder drug,”
with its best effect against gram-positive bacteria.
5. Selman Waksman soon discovered streptomycin, which worked very well against
gram-negative bacteria. At that point, many scientists believed (mistakenly) that we had
won the war against bacteria.
SOURCES OF ANTIBIOTICS
Most antibiotics come from soil bacteria. A great number of the antibiotics that are
discovered are so toxic that while they kill all known bacteria, they also kill the patient.
Only a small percentage can be developed for use in treating disease. Some organisms
that produce antibiotics are:
1. Members of the genus Streptomyces (bacteria)--more than half our antibiotics
2. Members of the genus Bacillus (bacteria)
3. Members of the genus Cephalosporium (fungus)
4. Members of the genus Penicillium (fungus)
TABLE 20.1 P. 550
SPECTRUM OF ANTIMICROBIAL ACTIVITY
The goal that must always be kept in mind is that the antimicrobial must cause more
harm to the pathogen than to the host. This is called selective toxicity. We have had our
greatest success with antibacterial antibiotics, since there are a number of things that are
different in procaryotic bacterial cells from the eucaryotic cells of the host. These
differences make it relatively easy to target the pathogen and spare the host. Attacking
the eucaryotic cells of fungi, helminths, and protozoa, and the host cells that viruses
have invaded is more difficult.
Antimicrobials may work against only certain microbes. They can be:
The spectrum of activity is the range of different microbes a drug is able to work
against. Narrow-spectrum means that the drug works best against only a certain group
or type; broad-spectrum drugs work against a wider range of microbes. If the drug
works against bacteria, a broad-spectrum drug would probably do well against both
gram-positive and gram-negative organisms. A narrow-spectrum drug would work
only against one or the other, or possibly an even narrower group.
An ideal antimicrobial would have more effect against pathogens and less on the normal
flora of the body. Unfortunately, this is not always possible.
ACTION OF ANTIMICROBIAL DRUGS
Antimicrobial drugs are either ---cidal, which means they actually kill the pathogens, or
----static, which means they slow or prevent reproduction. In either case, the defenses of
the host will also be needed.
1. INHIBITION OF CELL WALL SYNTHESIS—SINCE this attacks the cell wall, these drugs have
little effect on host cells, which do not contain peptidoglycan. Penicillin, bacitracin, and
vancomycin act in this way.
2. INHIBITION OF PROTEIN SYNTHESIS---since ribosomes of procaryotic cells are slightly
different from those of eucaryocytes, they can be used as a target. Chloramphenicol,
erythromycin, streptomycin, and the tetracyclines act in this way.
3. INJURY TO THE PLASMA MEMBRANE—this is a mode of action of both some
antibacterials and some antifungals. Antifungals are able to work mostly against fungus
cell membranes because they contain ergosterol instead of cholesterol. However, these
antibiotics are potentially quite toxic to the host. Examples are the polymixins, and
antifungals such as amphotericin B, miconazole, and ketoconazole.
4. INHIBITION OF NUCLEIC ACID SYNTHESIS---selective toxicity varies, but these interfere
with DNA replication and transcription. Rifampin and the quinolones are examples.
5. INHIBITING THE SYNTHESIS OF ESSENTIAL METABOLITES---the sulfas and trimethoprim
work this way. They interfere with the pathway by which bacteria synthesize folic acid.
Since humans produce folic acid by a different pathway, these drugs have less effect on
ANTIBACTERIAL CHART ON FOLLOWING PAGE:
DRUGS BY MODE OF ACTION COMMENTS
INHIBITORS OF CELL WALL
Penicillin G Gram-positive bacteria, injected. Bactericidal.
Penicillin V Gram-positive bacteria, oral. Bactericidal.
Ampicillin Broad spectrum. Bactericidal.
Methicillin Resistant to penicillinase. Bactericidal.
Aztreonam Gram-negative bacteria, including Pseudomonas. Bactericidal.
Cephalosporins Resistant to penicillinase; broad spectrum. Bactericidal.
Carbapenems (imipenim) -lactam type, very broad spectrum. Bactericidal.
Bacitracin Polypeptide type, gram-positive bacteria, topical use. Bactericidal.
Vancomycin Glycopeptide type, penicillin-resistant gram-positive bacteria. Bactericidal.
Isoniazid Mycobacteria (tuberculosis); inhibits synthesis of mycolic acid component
of the mycobacterial cell wall. Bacteriostatic.
Ethambutol Mycobacteria (tuberculosis).; inhibits incorporation of mycolic acid into
mycobacterial cell wall. Bacteriostatic.
INHIBITORS OF PROTEIN SYNTHESIS
Streptomycin Broad spectrum, including mycobacteria. Bacteriocidal.
Neomycin Topical use, broad spectrum. Bactericidal.
Gentamicin Broad spectrum, including Pseudomonas. Bactericidal.
Tetracylcine, oxytetracycline, Broad spectrum, including chlamydias and rickettsias; animal feed
Chlortetracycline additives. Bacteriostatic.
Chloramphenicol Broad spectrum, potentially toxic. Bacteriostatic.
Erythromycin Alternative to penicillin. Bacteriostatic.
INJURY TO THE PLASMA MEMBRANE
Polymixin B Topical use, gram-negative bacteria, including Pseudomonas. Bactericidal.
INHIBITORS OF NUCLEIC ACID
Rifampin Inhibits synthesis of mRNA; treatment of tuberculosis. Bactericidal.
Nalidixic acid, ciprofloxin Inhibits DNA synthesis; broad spectrum, urinary tract infections.
COMPETITIVE INHIBITORS OF THE
SYNTHESIS OF ESSENTIAL
Trimethoprim-sulfamethoxazole Broad spectrum; combination is widely used. Bacteriostatic.
MODE OF ACTION COMMENTS
Amphotericin B Injury to plasma membrane Systemic fungal infections.
IMIDAZOLES & TRIAZOLES Inhibition of plasma membrane Fungicidal.
Clotrimazole Topical use for fungal infections of
skin and mucous membranes.
Ketoconazole Topical use for fungal infections of
skin; orally for systemic fungal
Griseofulvin Inhibition of mitotic spindle. Rungal infections of skin. Fungistatic.
Tolnaftate Unknown. Athlete’s foot. Fungicidal.
Flucytosine Inhibits DNA or RNA synthesis. Systemic fungal infections.
Amantadine Blocks entry or uncoating. Influenza A prevention.
Acyclovir, ribavirin, Inhibit DNA synthesis by reverse Herpesvirus
ganciclovir, trifluoridine transcriptase
Nevirapine Binds to reverse transcriptase HIV infection
Indinavir, saquinavir Inhibit viral protease. HIV infection
-interferon Inhibits spread of virus to new cells. Viral hepatitis.
Chloroquine Inhibits DNA synthesis. Malaria, effective against red blood
cell stage only
Diiodohydroxyquin Unknown. Amoebic infections. Amoebicidal.
Metronidazole Damages DNA. Amoebicidal & trichomonicidal.
Niclosamide Prevents ATP generation in Kills tapeworms
Praziquantel Alters permeability of plasma Kills flatworms. Tapeworm and fluke
Pyantel pamoate Neuromuscular block. Intestinal roundworms. Kills
TESTS TO GUIDE CHEMOTHERAPY
Although in many cases chemotherapy is begun by guessing which drug might be
effective, tests to determine effectiveness are sometimes used. This might be necessary
when drug resistance is a problem, or when the patient has not responded to the first
1. The Kirby-Bauer diffusion (disk diffusion) method—this is what we did in lab. After
inoculating the trouble-making organism onto an agar plate, discs containing various
antibiotics are applied to the surface and zones of inhibition are observed.
2. The E test—this determines the minimal inhibitory concentration (MIC). The lower the
concentration that is effective, the better the chance for good results in a patient. A
plastic-coated strip contains a gradient of antibiotic concentrations and can be read after
3. Broth dilution tests---this is another way to determine the minimum inhibitory
concentration that is effective. This involves use of a series of broth cultures, each
containing a different concentration of the antibiotic.
EFFECTIVENESS OF CHEMOTHERAPEUTIC AGENTS
What do bacteria do that makes them resistant to an antibiotic?
1. Microbes release an enzyme that modifies or destroys the antibiotic. Penicillinase is an
example of this.
2. Something about the microbe changes and makes it difficult or impossible for the
antibiotic to penetrate into the bacteria. This often is a change in the outer membrane.
3. The microbe develops a way to pump out the antibiotic so fast it does little harm.
Many organisms can pump out tetracyclines, for example.
4. Microbe develops an alternate chemical reaction to the one the antibiotic blocks.
5. Microbe may make a slight change in whatever cell component the antibiotic attacks.
Many of these changes are due to random mutations. Once even one microbe becomes
resistant, it passes the resistance on. If only microbes that are resistant survive, the entire
population of microbes soon becomes resistant.
Another major problem with resistance is that the genes that make an organism resistant
are often carried on a plasmid. The R plasmids are often shared among bacteria,
increasing the resistance problem.
Many bacterial diseases are now very commonly resistant to antibiotics, and there are
strains of pathogenic bacteria that are resistant to all known antibiotics.