Antimicrobial Drugs
I. Terminology of chemotherapy
II. Where antimicrobial drugs come from
III. How antimicrobials work
IV. Drug resistance
V. Interactions between drugs and hosts
VI. Selecting the right antimicrobial drug
I. Terms
When a drug is used to control an infection, the
practice is termed antimicrobial chemotherapy
Antimicrobial drugs: a class of compounds which
inhibit or kill microorganisms.
– Antibiotics -- _____________ antimicrobial drugs.
– Synthetics -- ______________ antimicrobials.
Antibiotics which have been chemically modified are
called _________________.
– Broad spectrum agents -– Narrow spectrum agents --
Where do antimicrobials come
from?
•
Fleming’s discovery of _______________
•
Main sources of useful antibiotics: Streptomyces
and Bacillus (____________), Penicillium and
Cephalosporium (_________)
•
Thousands have been discovered; relatively few
of these are ___________.
How do they work?
•
The main trick if one were to “design” an antibiotic: find
something the target pathogen has or does (e.g. a structure or
pathway) which the host cell doesn’t. For example, most bacteria
have peptidoglycan while eukaryotes don’t so a compound which
destroys it or inhibits its production (like penicillin) shouldn’t
affect eukaryotes.
•
Toxicity to the host is a major concern
Therapeutic Index -- ratio of a drug’s_________ _________ to
its minimum __________________ dose. For example:
20 µg/ml toxic dose
= ____
16 µg/ml effective dose
versus
20 µg/ml
2 µg/ml
= ___
How do they work (cont.)?
Four main approaches:
1) Inhibition of ________ _______ formation -e.g. penicillin and cephalosporin
2) Inhibition of ________ ________ synthesis -e.g. sulfonamides
3) Inhibition of ___________ synthesis -- e.g.
tetracycline
4) Inhibition of cell ______________ function
(less common) e.g. polymixin
Cellular targets of antimicrobial drugs
•Penicillins
•Cephalosporins
•Vancomycin
•Bacitracin
•Novobiocin
•Nalidixic acid
•Rifampin
•Erythromycin
•Chloramphenicol
•Tetracyclines
•Aminoglycosides
(Streptomycin,
Kanamycin,
Gentamicin)
•Polymyxins
Inhibition of cell wall synthesis
Varies (and can be
modified)
Penicillin family
(“Beta-lactams”)
 Penicillin
 Amoxicillin
 Ampicillin
ß-_______
ring
 Carbenicillin
 etc.
Inhibition of cell wall synthesis (cont.)
Cephalosporins

First isolated from Cephalosporium acremonium

Similar to ___________ because also has ß-lactam ring:
(Also can be O)
R
S
NH
N
R
O
COOH
Most have
root “cef” in
name
Nucleic acid synthesis inhibitors
Chloroquine
Trimethoprim
Sulfanilamides (sulfa drugs)
Are metabolic ______________ of PABA (paraaminobenzoic acid), necessary for the synthesis of
folic acid. Folic acid is then required for the
synthesis of ___________ and ______________.
Sulfanilamide
Sulfanilamide
PABA
Folic acid
Sulfa competes with PABA for the active site
on the enzyme which converts PABA to
dihydrofolic acid, a precursor of folic acid
Protein synthesis inhibitors
Tetracyclines -- Semisynthetic drug derived from a natural
antibiotic made by Streptomyces. _______________binding, bacteriostatic, broad spectrum.
Erythromycin -- Ribosome-binding antibiotic derived from
Streptomyces erythraeus. Also bacterio_________ . In
antibiotic class known as “_________________”
Aminoglycosides (e.g. streptomycin, kanamycin,
gentimycin, neomycin). Also derived from
Streptomyces, also ribosome-binding but
bacteri_________.
Structure and derivatives of tetracycline
Two New Classes of Antibiotics
1) Fosfomycin -- phosphoric acid used
primarily against _____________________
due to enteric bacteria (E. coli, etc.)
2) Synercid (dalfopristin/quinupristin) and
Zyvox (linezolid)-- narrow spectrum drugs
used primarily against _________________
pathogens such as Staphylococcus,
Enterococcus, and Streptococcus.
Antimicrobial Drugs
I. Terminology of chemotherapy
II. Where antimicrobial drugs come from
III. How antimicrobials work
IV. Drug resistance
V. Interactions between drugs and hosts
VI. Selecting the right antimicrobial drug
Drug resistance mechanisms
1) Enzyme _____________ -- e.g. ß-lactamases
Enzyme inactivation (cont.)
The arms race: ß-lactamase inhibitors
These are not antimicrobial themselves but are prescribed in
conjunction with ß-lactam antibiotics to increase their
effectiveness. They tend to be expensive.
Other drug resistance mechanisms
2) Decreased permeability to the drug

Early penicillins could not pass the __________ _____________
of Gram-negatives
3) Altered ______________ for the drug -- altered cell wall
receptors, altered target proteins (e.g. altering 50S ribosomal binding
site for erythromycin)
4) Changes in metabolic pathways or enzymes -- e.g. alteration
in ________ _________ synthesis
5) Efflux __________ -- antibiotics can be pumped out as fast as they
come in. Pseudomonas are particularly famous for this.

_____________________ is pumped out of cells by plasmidencoded cytoplasmic membrane proteins
The emergence of antibiotic resistance
Relationship between antibiotic use and the percentage of bacteria isolated
from diarrheal patients resistant to the antibiotic
Percentage of reported cases of gonorrhea caused by
antibiotic-resistant strains
59000 cases
9000 cases
Appearance of antibiotic resistance in several human
pathogens since the beginning of antibiotic therapy
At Rockingham Memorial Hospital, for example, 88% of Staphylococcus aureus
strains isolated in 1999 were resistant to penicillin, ampicillin, and amoxicillin.
The Arms Race Continues: S. aureus
resistance to a brand-new antibiotic
07/20/2001
Associated Press
LONDON – In a frustrating development in the battle against drugresistant bacteria, scientists report that the first entirely new type
of antibiotic in 35 years has been beaten by the staph
supergerm little more than a year after being introduced.
Researchers at Harvard Medical School describe in the Lancet
medical journal this week how an 85-year-old man on dialysis
came down with a staph infection in the lining of his intestines
that was not vulnerable to the new drug, Zyvox [Linezolid]. It is
the first report of staph resistance to the medicine.
Antimicrobial Susceptibility Profiles of
Selected Aerobes,
Rockingham Memorial Hospital, 1999
Percent Susceptible
Organism
Staphylococc us
aure us
Staphylococc us
epidermidis
Streptococc us
pneumoniae
Pse udom onas
ae ruginosa
Esc herichia c oli
Klebsiella
pneumoniae
Numb er of
is olates
te sted
Ampicillin/
Amoxicillin
Augmentin
Cefoxit
in
Cefta zidime
Erythromycin
Gentamicin
Penicillin
Vancomycin
71 5
12
55
90
12
100
81
11
38
65
11
100
52
100
76
42
11 5
11 8
0
57
3
78
0
99
92
100
82
95
62
0
91
95
97
97
EXPOSURE TO DISINFECTANTS SUCH AS PINE-BASED CLEANERS
MAY CONTRIBUTE TO ANTIBIOTIC RESISTANCE
Repeated exposure to household cleaners containing pine oil may cause bacteria to
develop resistance to some common antibiotics, say researchers from Tufts
University School of Medicine in the December 1997 issue of the journal
Antimicrobial Agents and Chemotherapy.
In the study the researchers repeatedly exposed the bacteria Escherichia coli to a
household cleaner containing the disinfectant pine oil or pure pine oil itself in
order to isolate pine-oil resistant strains. The resistant strains were then tested
against a variety of antibiotics. All pine oil-resistant strains were also
multidrug resistant.
“To our knowledge, the selection of chromosomal antibiotic resistance, albeit low
level, by a disinfectant has not previously been reported for gram-negative
bacteria,” say the researchers. “Whether pine oil in products meant for
household use could lead to a significant problem of antibiotic resistance is not
know. However, it seems possible that additional disinfectants might be
capable of selecting for resistance to antibiotics and vice versa.”
(M.Moken, L.M. McMurry and S. Levy. 1997. Selection of multiple-antibioticresistant mutants of Escherichia coli by using the disinfectant pine oil: roles of
the mar and acrAB loci. Antimicrobial Agents and Chemotherapy. 41:27702772.)
Host/drug reactions (adverse or “side” effects)
Tissue toxicity -- kidneys, liver, heart, skin, nerves,
teeth and bones
_____________ reactions
•
•
sensitized on first contact.
often due to reaction to a metabolic byproduct
Disruption of normal flora (‘mucking with the
microbial ecology of our bodies’)
•
frequent cause of diarrhea
•
____________________ -- secondary infection caused
by destruction of normal microflora.
Example: yeast (Candida albicans) infections caused by
destruction of vaginal lactobacilli with broad-spectrum
antibiotics
Picking the right antimicrobial drug
1) Identify (if possible) the agent
2) Determine (if possible) the _______________
of the agent -- e.g.
 Kirby-Bauer
 tube
susceptibility test (will do in lab)
dilution test
Minimum Inhibitory Concentration = minimum
concentration of a drug that visibly __________ ________.
Tube dilution test
Minimum Inhibitory Concentration (MIC)