Chapter 24

Antimicrobial Drugs
 24.1 The History and Properties of
Antimicrobial Agents
• The history of chemotherapy originated with Paul
Ehrlich.
• Ehrlich originated the concept of selective toxicity.
• Ehrlich and Sahachiro Hata discovered the
effectiveness of arsphenamine (Salvarsan)
against the syphilis spirochete.
• Prontosil was a red dye found to inhibit some
gram-positive bacterial species.
• Alexander Fleming’s serendipitous discovery of
penicillin ushered in the era of antibiotics.
• Penicillium mold produces a substance that kills
gram-positive bacteria.

FIGURE 24.2b: Photograph of Fleming’s

FIGURE 02a: Alexander Fleming and his culture plate
culture of Penicillium
© National Library of Medicine
© Science Source, photo by Dean Pausett/Photo
Researchers, Inc.
• Antimicrobial agents have a number of important
properties.
• Synthetic agents are made in a pharmaceutical
lab.

• Antibiotics are products of or derived from living

microorganisms.

• Semisynthetic drugs include synthetic and

antibiotic elements.
• Selective toxicity means that a drug should harm the
pathogen but not the host.
• The toxic dose of a drug is the concentration causing
harm to the host.
• The therapeutic dose is the concentration eliminating
pathogens in the host.
• Together, the toxic and therapeutic doses are used to
formulate the chemotherapeutic index.

FIGURE 03: A representation of the chemotherapeutic index

• Drugs have a range of pathogens on which they will
work (antimicrobial spectrum).
• Broad-spectrum drugs affect many taxonomic groups.
• Narrow-spectrum drugs affect only a few pathogens.

FIGURE 04: The antimicrobial spectrum of activity

 24.2 The Synthetic Antibacterial Agents
• Sulfanilamide and other
sulfonamides target
specific metabolic
reactions.
• Sulfonamides out
compete essential folic
acid components for
binding sites in a
bacterial enzyme.

• They prevent nucleic

acid synthesis and DNA FIGURE 05: The disruption of folic acid
replication. synthesis by competitive inhibition
• Other synthetic antimicrobials have additional
bacterial cell targets.
• Isoniazid interferes with cell wall synthesis in
species of Mycobacterium.
• Quinolones block DNA synthesis in bacteria.

FIGURE MM06: Ciproflozacin

FIGURE MM05: Isoniazid
24.3 The Beta-Lactam Family of Antibiotics
• Penicillin has remained the most widely used
antibiotic.
• Penicillins are active against many gram-positive
and some gram-negative bacteria.
• They interfere with cell wall synthesis, causing the
cell to burst.
FIGURE 06: Some
members of the penicillin
group of antibiotics
• Some individuals experience an anaphylactic allergic
reaction.
• Many penicillin-resistant species produce beta-
lactamases that inactivate penicillin.

FIGURE 07: The action of penicillinase on sodium penicillin G

• Numerous semisynthetic penicillins have been

developed.
• Other beta-lactam antibiotics also inhibit cell wall synthesis.
• Cephalosporins are broader spectrum alternatives to
penicillins.
• Monobactams are active against aerobic, gram-negative
rods.
• Carbapenems are broad spectum drugs.
• For example, Imipenem

Figure MM07: Cephalosporin FIGURE MM08: Imipenem

 24.4 Other Bacterially Produced
Antibiotics
• Vancomycin also
inhibits cell wall
synthesis.
• It is effective against
gram-positive
bacteria such as
staphylococci.
• Side effects include
damage to the ears
and kidneys. FIGURE 10: The targets for antibacterial agents
Polypeptide antibiotics affect the cell membrane.

• Bacitracin interferes with

transport of cell wall precursors
through the membrane.
• It is toxic internally, so is used FIGURE MM10: Bacitracin
topically.

• Polymyxins increase
membrane permeability of
gram-negative rods.

FIGURE MM09: Vancomycin

• Many antibiotics affect protein
pynthesis.
• Aminoglycosides attach to
bacterial ribosomes, blocking
transcription.
• Streptomycin is sometimes FIGURE MM11: Streptomycin
used in tuberculosis cases.
• Gentamicin is used against
gram-negative infections in
the urinary tract.
• Neomycin is used as an
ointment in combination with
polymyxin and bacitracin as
Neosporin. FIGURE MM12: Gentamicin
• Chloramphenicol is used against a wide variety of
bacteria and some rickettsiae and fungi.
• It is reserved for serious infections like:
– meningitis;
– cholera;
– typhoid and typhus fevers;
– Rocky Mountain spotted fever.
• Severe side effects include aplastic anemia and gray
syndrome in newborns.
Figure 08:
Antibiotics and
Their Affect on
Protein Synthesis.
• Tetracyclines are broad spectrum antibiotics that
target the attachment of tRNA to the 30S subunit.
• They have a benzene ring formation.
• They can destroy intestinal microbiota and cause staining
of the teeth.

FIGURE 09b: The staining of teeth

FIGURE 09a: The structure of doxycycline associated with tetracycline use
© Kenneth E. Greer/Visuals Unlimited
• The macrolide erythromycin is used against
gram-positive bacteria.

• Clindamycin is a semisynthetic drug used

against penicillin-resistant bacteria.
• Pseudomembranous colitis can occur.

• Streptogramins are effective against gram-

positive bacteria.
• Oxazolidinones (like Zyvox) are effective
against gram-positive bacteria, including
multidrug-resistant Staphylococcus aureus,
killed, allowing Clostridium difficile to flourish.

• Some antibiotics inhibit nucleic acid synthesis.

• Rifampin interferes with RNA synthesis.
• It is effective against tuberculosis, leprosy,
and meningitis.
• It can cause liver damage.
 24.5 Antifungal and Antiparasitic Agents
• Several Classes of Antifungal Drugs Cause Membrane
Damage
• Polyenes bind to ergosterol in fungal plasma membranes,
causing contents to leak out.
• Nystatin is used against Candida albicans infections.
• Amphotericin B is used against serious systemic fungal
infections.

• Imidiazoles inhibit an enzyme needed to form ergosterol in

the fungal plasma membrane.
• They are used for cutaneous and systemic infections.
• Echinocandins inhibit fungal cell wall synthesis.
• Caspofungin is used to treat invasive
candidiasis and aspergillosis.

• Flucytosine interrupts nucleic acid synthesis.

• It is active against strains of Candida and
Cryptococcus.

• Griseofulvin binds to microtubules, inhibiting

mitosis.
• It is used against ringworm and athlete’s foot.
• The goal of antiprotozoal agents is to eradicate the
parasite.
• Aminoquinolines are antimalarial drugs that accumulate
in parasitized red blood cells.
• They interfere with the parasite’s ability to break down
and digest hemoglobin.

• Sulfonamides block folic acid synthesis as they do for

bacteria.

• Nitroimidazoles interfere with DNA synthesis.

• They are used to treat amebiasis, giardiasis and
trichomoniasis.
• A derivative of arsenic is used against African
trypanosomiasis.
• A derivative of antimony is used against leishmaniasis (as is
pentamidine).
• Artemisinin destroys malarial
parasites by releasing free
radicals in red blood cells.
FIGURE
MM25:
Artemisnin

FIGURE 12: The source of artemisinin

© Jack Barker/Alamy Images
• Antihelminthic agents are targeted at nondividing
helminths.
• Praziqyantel changes membrane permeability in
cestodes and trematodes.
• This causes contraction and paralysis in the parasite.
• Mebendazole:
• inhibits nutrient uptake in worms
in the host intestine.
• disrupts microtubules and cell
division.
• Avermectins cause paralysis
in a number of roundworms.

FIGURE MM26: Praziquantel

24.6 Antibiotic Assays and Resistance
• There are several
antibiotic susceptibility
assays.
• The tube dilution
method determines
the minimum
inhibitory
concentration.
FIGURE 13ab: Determination of minimal
inhibitory concentration
Source: Data modified from the International
Journal of Applied Research in Veterinary
Medicine.
 • The agar disk diffusion method involves different antibiotics
diffusing from paper disks in a bacterial colony.

FIGURE 14: Antimicrobial susceptibility testing

Courtesy of Dr. Richard Facklam/CDC
• There are four mechanisms of antibiotic resistance.
• Many species of bacteria have evolved
resistance to certain antibiotics and synthetic
agents.
• The evolution of strains of S. aureus resistant
to multiple drugs is particularly alarming.

1. Resistance to sulfonamides may develop if the

bacterial enzyme changes or if the bacteria
evolves an alternate metabolic pathway.

2. Bacteria may evolve the ability to enzymatically

inactivate an antibiotic.
3. Bacteria may evolve the ability to prevent drug
entry into the cytoplasm or to pump the drug out
of the cytoplasm.
4. Bacteria can evolve changes in drug targets like
ribosomes or enzymes involved in replication.
Figure 16: Types of
Antibiotic Resistance.
• Antibiotic resistance is of
grave concern in the
medical community.
• Improper or excessive
use of antibiotics
causes antibiotic
resistance.

• If resistant strains spread

to other patients, a
superinfection occurs.

Figure 17: The Possible Outcomes of Antibiotic Treatment.

• Antibiotics are available over the counter in
developing countries, allowing for overuse
and incorrect use.
• Antibiotic use is widespread in livestock
feeds.
• They can be transmitted to humans
through meat consumption.
Figure 19: Annual Global
Production of Antibiotics.