chapter 14

There’s evidence that humans have been exposed to
antimicrobial compounds for ….

millenia

Early 1900s – Paul Ehrlich and his assistant Sahachiro
Hata found

compound 606 – killed Treponema pallidum -
sold under the name of Salvarsan.

1928 Alexander Flemming

discovered penicillin, the first
natural antibiotic

1930s - Klarer, Mietzsch, and Domagk discovered

prontosil
– killed streptococcal and staphylococcal infections.
▪ The active breakdown product of prontosil is
sulfanilamide
▪ Sulfanilamide was the first synthetic antimicrobial
created.

Early 1940s – Dorothy Hodgkin –

determined the structure of
penicillin using x-rays.
▪ Scientists could then modify it to produce
semisynthetic penicillins.

1940s – Selman Waksman’s research team discovered

several antimicrobials produced by soil microorganisms.

chemotherapeutic agent or drug

any chemical agent
used in medical practice

antibiotic agent

considered to be a
chemical substance made by a microorganism that can
inhibit the growth or kill microorganisms

antimicrobic or antimicrobial agent

a chemical
substance similar to an antibiotic, but may be synthetic

Antibiotic

usually one bacterial target; e.g. a key
bacterial enzyme is blocked.

Antimicrobial

a broad term but often can mean multiple
targets; e.g. membranes and DNA

Selective toxicity

harms microbes but not damaging the host

Chemotherapeutic index

maximum tolerable dose per Kg of
body weight/minimum dose per Kg of body weight which cures
the disease

Antimicrobial drugs are classified based by ?

the type of organism they affect

Narrow spectrum

targets only specific subsets of bacterial
pathogen

broad spectrum

targets a wide variety of bacterial pathogens –
including Gram-positive and Gram-negative species.

development of superinfections

1. normal microbiota keeps opportunistic pathogens in check

2. broad spectrum antibiotics kill nonresistant cells

3. drug resistant pathogens proliferate and can cause a superinfection

types of antibiotic activity

1. bacteriostatic

2. bacteriocidal

3. bacteriolytic

minimal inhibitory concentration

the lowest concentration
of the drug that will prevent the growth of an
organism

The in vitro effectiveness of an agent is
determined by?

how little of it is needed to stop
growth

minimum bactericidal concentration (MBC) is
determined by…

using a tube dilution test and removing
the antibiotic

If cells grow in the fresh medium without antibiotic, the
drug …

is bacteriostatic

if cells do not grow, the drug is…

bactericidal

either the MIC test nor the Kirby-Bauer test can
distinguish whether the drug is…

bacteriostatic or bactericidal

Attributes of an ideal antimicrobial

1. Solubility in Body fluids.
2. Selective toxicity
3. Toxicity not easily altered
4. Non-allergenic
5. Stability
6. Resistance by microorganisms not easily
acquired
7. Long shelf-life
8. Reasonable cost

Dosage

mount of medication given during a certain
time interval.
▪ In children, dosage is based upon the patient’s
mass
▪ In adults a standard dosage is used, independent
of mass

half life of antibiotic

Rate at which 50% of a drug is eliminated from
the plasma.

when choosing an antibiotic to prescribe, the clinical needs to keep in mind:

▪ whether the organism is susceptible to the antibiotic
▪ whether the attainable tissue level of the antibiotic is
higher than the MIC
▪ the understanding of the relationship between the
therapeutic dose and the toxic dose of the drug

Synergistic drugs

may work poorly when they are given
individually but very well when combined (combined
effect is greater than additive effect).
example: aminoglycoside + vancomycin

antagonistic drugs

the mechanisms of action of antagonistic drugs interfere
with each other and diminish their effectiveness.
example: penicillin + macrolides

How Do Antibiotics Work?

Antibiotics exhibit selective toxicity because they disturb
enzymes or structures unique to the target cell

antibiotic mechanisms include:

• cell wall synthesis
• cell membrane integrity
• DNA synthesis
• RNA synthesis
• protein synthesis
• metabolism

antibiotics that target the cell wall

1. penicilin

2. cephalosporins

penicilins

• The enzymes that attach the disaccharide units to
preexisting peptidoglycan and produce peptide cross links
are collectively called penicillin-binding proteins (PBPs).
• Without an intact cell wall, the growing cell eventually bursts
due to osmotic effects.
• Thus, penicillin is a bactericidal drug.

cephalosporins

• Beta-lactam antibiotic originally discovered in nature but
modified in the laboratory, a type of semisynthetic drug.
• Chemists have modified the basic structure of
cephalosporin in ways that improve the drug’s
effectiveness against penicillin-resistant pathogens.
• Each modification is a new “generation” of
cephalosporins. There are currently 5 generations of this
antibiotic

inhibitors of cell wall synthesis

1. polypeptide antibiotics

2. antimycobacterial antibiotics

polypeptide antibiotics

1. bacitracin

2. vancomycin

bacitracin i

 Topical application
 Against gram-positives

vancomycin

 Glycopeptide
 Important “last line” against antibiotic-resistant
S. aureus

antimycobacterial antibiotics

1. isoniazid

2. ethambutol

Isoniazid (INH)

 Inhibits mycolic acid synthesis

Ethambutol

Inhibits incorporation of mycolic acid

antibiotics that target the bacterial membrane

1. polymyxin

2. tyrocidin

3. platansimycin

4. gramicidin: cyclic peptide

Polymyxin, Tyrocidin and Platansimycin

• Act as detergents and disrupt the structure of the cell
membrane by binding to the phospholipids.
• Mode of action
• Interacts with lipopolysaccharide in the outer
membrane of gram- negative bacteria, killing the cell
through the eventual disruption of the outer
membrane and cytoplasmic membrane
• Highly toxic

Gramicidin - Cyclic peptide

Mode of action
• Inserts into the
cytoplasmic
membrane of gram-
positive bacteria,
disrupting the
membrane and killing
the cell

antibiotics that affect dna synthesis and integrity

1. metronidazole

2. sulfonamides

3. quinolones

metronidazole

activated after being metabolized by microbial protein cofactors ferredoxin found in anaerobic and
microaerophilic bacteria such as Bacterioides and
Fusobacterium.
• Aerobic microbes are resistant because they do not possess
the electron transport proteins capable of reducing
metronidazole

Sulfonamides

act to inhibit the synthesis of
nucleic acids by preventing the synthesis of folic acid, an
important cofactor in the synthesis of nucleic acid
precursors.
• All organisms use folic acid to synthesize nucleic acids.
Bacteria make folic acid from the combination of PABA,
glutamic acid, and pteridine. Mammals do not synthesize
folic acid and must get it from the diet or microbes

quinolones

• DNA gyrase bound to and inactivated by a quinolone will
block progression of a DNA replication fork.
• Because bacterial DNA gyrases are structurally distinct
from their mammalian counterparts, quinolone antibiotics
will not affect mammalian DNA replication.

Rifampin

RNA synthesis inhibitor

best-known member of the rifamycin
family of antibiotics that selectively binds to bacterial RNA
polymerase and prevents transcription.
• Rifampin is also used to treat tuberculosis and
meningococcal meningitis

The major classes of protein synthesis inhibitors
target the ____ or ___ subunits of cytoplasmic ribosomes

30S or 50S

Drugs that affect the 30S ribosomal
subunit

1. aminoglycosides

2. tetracyclines

3. glycylcyclines

aminoglycosides

streptomycin, gentamicin, tobramycin)
Cause misreading of mRNA and inhibit peptidyl-
tRNA translocation.

tetracyclines

(doxycycline)
Bind to the 30S subunit and prevent tRNAs
carrying amino acids from entering the A
site.

glycylcyclines

(tigecycline)
Bind to 30S subunit and inhibit the entry of
aminoacyl-tRNA into the A site; able to function
in tetracycline resistant cells.

Drugs that affect the 50S ribosomal
subunit

1. chloramphenicol

2. macrolides

3. lincosamides

4. oxazolidinone

5. streptogramins

chloramphenicol

Prevents peptide bond formation by inhibiting
peptidyltransferase in the 50S subunit

macrolides

(erythromycin, azithromycin, clarithromycin)
Bind to 50S subunit and inhibit translocation of tRNA
from the A site to the P site.

lincosamides (clindamycin)

Bind to peptidyltransferase and prevents peptide bond
formation from the ribosome.

oxazolidinones

Bind to 50S subunit and prevent assembly of the 70S
ribosome

streptogramins

(quinupristin, dalfopristin)
Bind to 50S subunit and block tRNA entry into the A site
while blocking exit of a growing protein from the ribosome.

Mechanisms of drug resistance

1. Drug modification or Inactivation
-By enzymes
2. Blocked penetration
-Altering porins in the outer membrane
3. Efflux pumps
-Altering porins in the outer membrane
4. Target modification
-Mechanism allows a formerly inhibited reaction
to occur

5.. Target overproduction
microbe overproduces the target enzyme such
that there is a sufficient amount of antimicrobial-
free enzyme to carry out the proper enzymatic
reaction.
6. Enzymatic bypass
microbe develops a bypass that circumvents the
need for the functional target enzyme
7. Target mimicry
production of proteins that bind and sequester
drugs, preventing the drugs from binding to their
target

Individuals can take the following actions to help fight drug resistance:

• frequent hand washing
• vaccinations
• avoiding use of antibiotics for viral infections
• refusing leftover antibiotics
• take full course of antibiotics prescribed

The influenza virus contains:

1. hemagglutinin

2. neuraminidase

Hemagglutinin

binds to the host membrane
receptors for entry by phagocytosis

Neuraminidase

cleaves sialic acid to allow virus
particles to escape from infected cells

Amantadine

prevents the virus from uncoating and exiting by
changing the pH of the phagolysosome

Oseltamivir (Tamiflu) and zanamivir (Relenza)

neuraminidase inhibitors prevent the virus particles from leaving the cell.

protease inhibitors

target the HIV protease
enzyme
Nelfinavir (Viracept) and lopinavir (Kaletra)

entry inhibitors

block virus envelope protein gp120
from binding to the host receptor CCR5
CCR5 inhibitors (maraviroc)

available anti fungal agents

1. polyenes

2. azoles

3. allylamines

4. echinocandins

5. griseofulvin

6. flucytosine

polyenes

Disrupts
membrane integrity

azaleas

Interferes with ergosterol
synthesis.

allylamines

Interferes with
ergosterol synthesis.

echinocandins

Blocks fungal cell wall
synthesis

griseofulvin

Blocks cell division.

flucytosine

inhibits DNA synthesis

Antiprotozoan agents

1. metronidazole

2. quinine

3. chloroquinine, primaquine

Metronidazole

causes DNA breakage. Used to treat
giardisis and Trichomonas infections.

Quinine

commonly used in the past, now used as a last
resort to treat malaria

chloroquinine, primaquine

interfere with
protein synthesis, specially red-blood cells

Antihelminthic agents

1. niclosamide

2. praziquantel

3. mebendazole and albendazole

4. ivermectin

Niclosamide

Prevents ATP generation
Tapeworms

Praziquantel

Alters membrane permeability
Flatworms

Mebendazole and albendazole

Interfere with nutrient
absorption
Intestinal roundworms

Ivermectin

Paralysis of helminths
Intestinal roundworms