Chapter 13.

Antimicrobial
Chemotherapy
• The principle of selective toxicity:
o The use of chemical substance to kills the harmful microbes without
damaging the host
o Anti-bacterial therapy has high selective toxicity and low treatment
toxicity, while antiviral and anti-eukaryotic treatments are low in selective
toxicity and high in treatment toxicity to the patient
• Antibiotics
o Definition and Origin: Chemicals produced by microorganisms that inhibit
or kill the growth other microorganisms. Microbes used to produce
commercial antibiotics: Streptomyces and Bacillus (all soil
bacteria); Penicillium and Cephalosporium (molds)
o Spectrum of activity: broad vs. narrow-spectrum antibiotics, with respect
to cell wall differences (G+, G-, TB) and groups of intra-cellular parasites
(Chlamydias and Rikettsias)
o Modes of action: Inhibition of cell wall synthesis (Penicillin); disruption
of membrane function (Polymyxin); Inhibition of protein synthesis
(Tetracycline); Inhibition of nucleic acid synthesis (Rifamycin); Anti
metabolites (Sulfa drugs)
o Side Effects: Toxicity to human cells; Allergic reactions of patients;
Disruption of normal microflora (harmless, protective bacterial
populations living with the human body, e.g., skin and gut microbes)
• Resistance of Microorganisms
o Non-genetic resistance: TB infection in regions of lung out of the reach of
host defense and treatment; endospore formation of Clostridium;
formation of biofilm (bacterial communities growing underneath a slime
protective layer) in medical devices (contact lens, artificial heart valves)
o Genetic resistance: Resistance due to mutations. Resistance mutations are
selected, not created, by antibiotics. R(resistance) plasmids carry multiple
resistance genes on a single plasmid and spread among a wide range of
bacterial species by phages (transduction).
o Molecular mechanisms of genetic resistance: Alterations in antibiotic-
binding sites, membrane transport system, enzyme specificity, and
metabolic pathway; development of antibiotic-degradation enzymes, e.g.,
beta-lactamase, which inactivates penicillin.
• Antibiotic resistance in hospitals
o Common resistance strains of bacteria in hospitals: methicillin-resistant
Staphylococcus aureus (MRSA), Salmonella, Neisseria, Pseudomonas
o Hospital conditions promoting drug-resistance include: proximity of
multiple pathogens, susceptible host population, and intensive antibiotics
use
 o Measures of limiting drug-resistance: limit antibiotic use; use targeted,
narrow-spectrum antibiotics; avoid premature termination of antibiotic
treatment (complete the treatment dosage to kill off the most resistant
cells)
• Determination of bacterial sensitivity to an antibiotic
o Disk-diffusion method. MIC (minimum inhibition concentration): the
lowest antibiotic concentration that prevents visible bacterial growth.
o Dilution method. MBC (minimum bactericidal concentration): lowest
concentration that kills bacterial cells.
o Automated methods: the use of manufactured trays preloaded with
species-identification agents or different concentrations of antibiotics, for
testing patient samples. These tests can quickly identify the pathogen as
well as its sensitivity to a variety of antibiotics.
• Antibacterial drugs: bactericidal (killing) or bacteriostatic (inhibitory)
o Inhibition of cell wall synthesis: penicillin; effective against actively
growing bacteria; narrow spectrum (G+); little toxicity to host cells
o Inhibition of protein synthesis: erythromycin, tetracycline; target 70S
prokaryotic ribosomes, thereby providing selective toxicity; broad
spectrum; side effect: disrupt normal microflora
o Injury to plasma membrane: polymyxin B, effective against G- (targeting
outer membrane)
o Inhibition of nucleic acid synthesis: rifampin; rarely used because of a
lack of selective toxicity
o Inhibition of synthesis of metabolites: sulfa drugs inhibit the synthesis of
folic acid, an essential vitamin used for nucleic acid synthesis. Humans
obtain folic acid from food so are not affected by inhibition of folic acid
synthesis.
• Antiviral drugs: inhibit viral growth, but do not eradicate viral infection or cure
the viral disease
o Nucleoside and nucleotide analogs: These "fake" nucleotides cause high
mutation rate of viruses, or inhibit enzymes for nucleic acid synthesis
(e.g., AZT inhibits the reverse transcriptase of HIV, brand name
Zidovudine)
o Other enzyme inhibitors: protease (an enzyme that cuts up a large protein
into fragments, which are then assembled into viral particles) inhibitors
(e.g., Indinavir) for treating HIV infection
o Combined treatment for HIV: reverse transcriptase inhibitor + protease
inhibitor, more effective then single-drug treatment, because viruses
resistant to both drugs are much less likely to emerge.
o Interferons: natural anti-viral proteins produced by human cells. For
hepatitis treatment.
• Antifungal, antiprotozoan, and antihelminthic drugs: parasites and humans have
similar cells (both eukaryotes) so these agents have low selective toxicity and
strong toxic side effects to the patient.