Antimicrobial Drugs
Antimicrobial Drugs
 Chemicals used to treat microbial infections
 Before antimicrobials, large number of people died
from common illnesses
 Now many illnesses easily treated with antimicrobials
 However, many antimicrobial drugs are becoming less
useful
Antimicrobial Drugs
 Chemotherapeutic agent=
 Antimicrobial drug=
 Different types of antimicrobial drugs:
 Antibacterial drugs
 Antifungal drugs
 Antiprotozoan drugs
 Antihelminthic drugs
Paul
Ehrlich
 He observed
that certain dyes stain bacterial cells and
not animal cells
 Theorized that there could be a dye or chemical that
would harm bacterial cells but not human cells
 Systematic search for chemical to cure syphilis
 606th compound tested proved to be highly effective in
treating laboratory animals
Gerhard Domagk
 Discovered red dye, Prontosil effective in treating
Streococcal infections in animals
 No effect in test tubes
 Enzymes in animals blood split Prontosil molecule
into sulfanilamide- this acted against streptococcal
 Sulfa Drug
Alexander Fleming
 Working on cultures of Staphylococcus
 Contamination with mold
 Noticed colonies growing near mold looked odd
 Found that mold was secreting substance that was
killing bacteria
Figure 20.1
Features of Antimicrobial Drugs


1.
2.
3.
4.
Most modern antibiotics come from species of
microorganisms that live in the soil
To commercially produce antibiotic:
Select strain and grow in broth
When maximum antibiotic concentration reached,
extract from medium
Purify
Chemical alter to make it more stable
Features of Antimicrobial Drugs:
Selective
Toxicity
 Cause greater harm to microorganisms than to host
 Chemotherapeutic index= lowest dose toxic to patient
divided by dose typically used for therapy
Features of Antimicrobial Drugs: Antimicrobial
Action
 Bacteriostatic: inhibit growth of microorganisms
 Bactericidal: Kill microorganisms
Features of Antimicrobial Drugs:
Spectrum of Activity
 Antimicrobial medications vary with respect to the
range of microorganisms they kill or inhibit
 Some kill only limited range : Narrow-spectrum
antimicrobial
 While others kill wide range of microorganisms:
Broad-spectrum antimicrobial
Features of Antimicrobial Drugs:
Effects of Combining Drugs
 Combinations are sometimes used to fight infections
 Synergistic: action of one drug enhances the activity of
another
 Antagonistic: activity of one drug interferes with the
action of another
Features of Antimicrobial Drugs:
Adverse Effects
1.
2.
3.
Allergic Reactions: some people develop
hypersensitivities to antimicrobials
Toxic Effects: some antimicrobials toxic at high
concentrations or cause adverse effects
Suppression of normal flora: when normal flora
killed, other pathogens may be able to grow to high
numbers
Features of Antimicrobial Drugs:
Resistance to Antimicrobials
 Some microorganisms inherently resistant to effects of
a particular drug
 Other previously sensitive microorganisms can
develop resistance through spontaneous mutations or
acquisition of new genes
Mechanisms of action of Antibacterial
Drugs
1.
2.
3.
4.
5.
Inhibit cell wall synthesis
Inhibit protein synthesis
Inhibit nucleic acid synthesis
Injury to plasma membrane
Inhibit synthesis of essential metabolites
Figure 20.2
b-Lactam Drugs- inhibit cell wall
synthesis
 Irreversibly inhibit enzymes involved in the final steps
of cell wall synthesis
 These enzymes mediate formation of peptide bridges
between adjacent stands of peptidoglycan
 b-lactam ring similar in structure to normal substrate
of enzyme
 Drug binds to enzyme, competitively inhibit
enzymatic activity
b-Lactam Drugs
 Some bacteria produce b-lactamase- enzyme that
breaks the critical b-lactam ring
 b-lactam drugs include: penicillins and
cephalosporins
Antibacterial medications that inhibit
protein synthesis
 Target ribosomes of bacteria
 Aminoglycosides: bind to 30S subunit causing it to
distort and malfunction; blocks initiation of
translation
 Tetracyclines: bind to 30S subunit blocking
attachment of tRNA
 Macrolides: bind 50S subunit and prevents
continuation of protein synthesis
Figure 20.4b
Antibacterial medications that inhibit
nucleic acid synthesis
 Target enzymes required for nucleic acid synthesis
 Fluoroquinolones: inhibit enzymes that maintain the
supercoiling of closed circular DNA
 Rifamycins: block prokaryotic RNA polymerase from
initiating transcription
Antibacterial medications injure plasma
membrane
 Polymyxin B: binds to membrane of G- bacteria and
alters permeability
 This leads to leakage of cellular contents and cell death
 These drugs also bind to eukaryotic cells to some
extent, which limits their use to topical applications
Antibacterial drugs that inhibit
synthesis of essential metabolites
 Competitive inhibition by substance that resembles
normal substrate of enzyme
 Sulfa drugs
Antiviral Drugs
 Very few antiviral drugs approved for use in US
 Effective against a very limited group of diseases
 Targets for antiviral drugs are various points of viral
reproduction
Nucleoside and Nucleotide analogs
 Acyclovir- used to treat genital herpes
 Cidofovir- used for treatment of cytomegaloviral
infections of the eye
 Lamivudine- used to treat Hepatitus B
Antiretrovirals
 Currently implies, a drug used to treat HIV
 Tenofovir- nucleotide reverse transcriptase inhibitor
 Zidovudine- nucleoside analog
Other enzyme inhibitors
 Zanamivir (Relenza) and Oseltamivir phosphate
(Tamiflu)- inhibitors of the enzyme neuominidase
 Used to treat influenza
 Indinavir- protease inhibitors
Interferons
 Cells infected by a virus often produce interferon,
which inhibits further spread of the infection
 Alpha-interferon- drug for treatment of viral hepatitis
infections
Antifungal drugs
 More difficult to find point of selective toxicity in
eukaryotes than in prokaryotes
 Targets of antifungal drugs:
 Agents affecting fungal sterols
 Agents affecting fungal cell walls
 Agents inhibiting nucleic acids
Agents affecting fungal sterols
 Many antifungals target the sterols in the plasma
membrane
 Polyenes- used in systemic fungal infections, very toxic
to kidneys
 Azoles- used for athlete’s foot and vaginal yeast
infections (miconizole)
Agents affecting fungal cell walls
 primary target of selective toxicity is β-glucan
 Inhibition of synthesis of this glucan results in an
incomplete cell wall, and results in lysis of the cell
 Caspofungin- first new class of antifungals in 40 years
Agents inhibiting nucleic acids
 Flucytin- nucleotide analog of cytosine, interferes with
the biosynthesis of RNA, and therefore protein
synthesis
Antiprotozoan drugs
 Quinine still used to control malaria
 Chloroquinone- synthetic derivative has largely
replaced it
 Mefloquinone- used in areas where resistance to
chloroquinone has developed
 Quinacrine- drug of choice for treating protozoan
disease, giardiasis
Antihelminthic drugs
 Praziquantel- used in treatment of tapeworms; kills
worms by altering permeability of plasma membranes
Kirby-Bauer method for determining
drug susceptibility
1.
2.
3.
4.
5.
Bacteria spread on surface of agar plate
12 disks, each with different antimicrobial drug,
placed on agar plate
Incubated- drugs diffuse outward and kill
susceptible bacteria
Zone of inhibition around each disk
Compare size of zone to chart
Figure 21.10
Resistance to antimicrobial drugs
 Drug resistance limits use of ALL known
antimicrobials
 Penicillin G: first introduced, only 3% of bacteria
resistant
 Now, over 90% are resistant
How
do
bacteria
become
resistant?
1. Spontaneous Mutation: happen as cells replicate
2.
Gene Transfer: Usually spread through conjugative
transfer of R plasmid
Slowing the emergence and spread of
antimicrobial resistance
1.
Responsibilities of Physicians: must work to identify
microbe and prescribe suitable antimicrobials, must
educate patients
2.
Responsibilities of Patients: need to carefully follow
instructions
Slowing the emergence and spread of
antimicrobial
resistance
3. Educate Public: must understand appropriateness and
limitations of antibiotics ; antibiotics not effective
against viruses
4. Global Impacts: organism that is resistant can quickly
travel to another country
- in some countries antibiotics available on nonprescription basis
- antibiotics fed to animals can select for drugresistant organisms
New Approaches to Antibiotic Therapy
Are Needed
 Scientists work to find new antibiotic targets in
pathogens
 Discovery of new and unique antibiotics is necessary