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?

Flemings 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 doesnt. For example, most bacteria
have peptidoglycan while eukaryotes dont so a compound which
destroys it or inhibits its production (like penicillin) shouldnt
affect eukaryotes.

Toxicity to the host is a major concern

Therapeutic Index -- ratio of a drugs_________ _________ to

its minimum __________________ dose. For example:

20 g/ml toxic dose

= ____

16 g/ml effective dose

versus

20 g/ml
2 g/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

-_______
ring

Carbenicillin
etc.

Inhibition of cell wall synthesis (cont.)

Cephalosporins

First isolated from Cephalosporium acremonium

Similar to ___________ because also has -lactam ring:

(Also can be O)

NH
N

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. -lactamases

Enzyme inactivation (cont.)

The arms race: -lactamase inhibitors

These are not antimicrobial themselves but are prescribed in

conjunction with -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
Per cent Susceptible

Organis m
Staphylococcus
aureus
Staphylococcus
epidermidis
Stre ptococcus
pneumoniae
Ps eudomona s
ae ruginosa
Es cherichia coli
Klebs ie lla
pneumoniae

Nu mb er o f
i so lates
tested

Ampicillin/
Amox icillin

Augmentin

Ce fox it
in

Ce ftazidime

Erythromyc in

Genta micin

Pe nicillin

Va ncomyc in

71 5

12

55

90

12

100

81

11

38

65

11

100

52

100

76

42
11 5
11 8

0
57

62

3
78

0
99

91

95

92
100

82
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)