Chapter 10 Controlling microbial growth in the body:

Antimicrobials

• Like disinfectants antimicrobial drugs act by killing or inhibiting the growth of microorganisms.

• Antimicrobial drugs must act within the body and show _______________________.

Antimicrobial Drugs

• Chemotherapy: the use of drugs to treat a disease

• Antimicrobial drugs: interfere with the growth of microbes within a host

• Selective toxicity: killing harmful microbes without damaging the host

Insert Table 20.1

Representative Sources of Antibiotics

Spectrum of Activity

• ________________: Antibiotic affects a large number of Gram-positive or Gram-negative bacteria

• ________________: Affective against a small range of organisms– Penicillin G affects Gram-positive bacteria but very

few Gram-negatives

The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs

Spectrum of Activity

– Use of broad spectrum drugs also destroy ______ _______________

– Survivors may become _______________– Yeast infections may arise from the over growth of

Candida albicans • _______________

– Term is also applied to growth of a target pathogen that has developed resistance to the antibiotic

– Antibiotic resistant strain replaces the original sensitive strain and the infection continues

• Antibiotics are only effective against ________ infections

• ________(flu) and ______________are _____ infections therefore antibiotics are ineffective!

Inhibition of Cell Wall Synthesis

– • Most common agents prevent cross-linkage of NAM

subunits• Beta-lactams are most prominent in this group

– Functional groups are beta-lactam rings– Beta-lactams bind to enzymes that cross-link NAM

subunits• Bacteria have weakened cell walls and eventually lyse

Inhibition or degrading bacterial cell walls.

Tetrapeptide side chain

Peptide cross-bridge

Carbohydrate“backbone”

Peptidebond

NAG

N-acetylmuramic acid (NAM)Side-chain amino acidCross-bridge amino acid

NAM

N-acetylglucosamine (NAG)

Structure of peptidoglycan ingram-positive bacteria

.

Inhibition or degrading bacterial cell walls.

• Penicillin's• Cephalosporin's• Vancomycin

The inhibition of bacterial cell synthesis by penicillin.

Rod-shaped bacterium before penicillin.

The bacterial cell lysing as penicillin weakens the cell wall.

• One of the most successful groups of antibiotics targets the synthesis of bacterial cell walls; why does the antibiotic not affect the mammalian cell?

The inhibition of protein synthesis by antibiotics.

Three-dimensional detail of the protein synthesis site showing the 30S and 50S subunit portions of the 70S prokaryotic ribosome

Diagram indicating the different points at which chloramphenicol, the tetracyclines, and streptomycin exert their activities

Translation

Streptomycin Tetracyclines

ChloramphenicolGrowing polypeptide

Messenger RNA

Direction of ribosome movement

70S prokaryotic ribosome

tRNA

Protein synthesis site

30S portion

50S portion

Changes shape of 30S portion,causing code on mRNA to beread incorrectly

Interfere with attachment oftRNA to mRNA–ribosome complex

Binds to 50S portion and inhibits formation of peptide bond

Protein synthesis

site Tunnel

Growing polypeptide

3′mRNA

30S

50S5′

Inhibitors of Protein Synthesis

– Prokaryotic ribosomes are 70S (30S and 50S)– Eukaryotic ribosomes are 80S (40S and 60S)– Drugs can selectively target translation– Mitochondria of animals and humans contain 70S

ribosomes • Can be harmful

Inhibitors of Protein Synthesis

• Chloramphenicol– Broad spectrum

• Binds 50S subunit; inhibits peptide bond formation

Inhibitors of Protein Synthesis

• Aminoglycosides– Streptomycin

• Broad spectrum– Change shape of 30S subunit

• Can have fatally toxic effects on Kidneys

• Tetracyclines– Broad spectrum

• Interfere with tRNA attachment– Side effects? Should Children take tetracycline?

• Children may experience a brown discoloration of teeth• Pregnant women may cause liver damage

– Most common antibiotic added to animal feed• Use results in significantly faster weight gain

Inhibitors of Protein Synthesis

Inhibition of nucleic acid replication and transcription

Inhibitors of Nucleic Acid Synthesis

– Several drugs block DNA replication or mRNA transcription

– Drugs often affect both eukaryotic and prokaryotic cells

– Not normally used to treat infections – Used in research and perhaps to slow cancer cell

replication

Inhibitors of Nucleic Acid Synthesis

• Rifamycin– Inhibits RNA synthesis– Antituberculosis

Injury to the plasma membrane of a yeast cell caused by an antifungal drug.

Injury to the Plasma Membrane

• Some drugs form channel through cytoplasmic membrane and damage its integrity

• Polymyxin B– Topical– Combined with bacitracin and neomycin in

over-the-counter preparation

– Antimetabolic agents can be effective when metabolic processes of pathogen and host differ

– Sulfonamides (sulfa drugs) Inhibit folic acid synthesis Broad spectrum

Inhibiting the Synthesis of Essential Metabolites: Antimetabolics

Inhibiting the Synthesis of Essential Metabolites: Antimetabolics

Figure 5.7bc Enzyme inhibitors.

Action of Enzyme Inhibitors

Competitiveinhibitor

Allostericsite

Alteredactive site

Noncompetitiveinhibitor

Major Action Modes of Antimicrobial Drugs.2. Inhibition of protein synthesis: chloramphenicol, erythryomycin, tetracyclines, streptomycin

Transcription Translation

ReplicationEnzyme

ProteinDNA mRNA

3. Inhibition of nucleic acid replication

and transcription: quinolones, rifampin

1. Inhibition of cell wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin

4. Injury to plasma membrane: polymyxin B

5. Inhibition of essential metabolite synthesis: sulfanimide, trimethoprim

Clinical Considerations in Prescribing Antimicrobial Drugs

• Routes of Administration– Topical application of drug for external infections– Oral route requires no needles and is self-

administered– Intramuscular administration delivers drug via

needle into muscle– Intravenous administration delivers drug directly to

bloodstream

Figure 10.13 The effect of route of administration on blood levels of a chemotherapeutic agent

Administration methodOral

Intramuscular(IM)

Continuousintravenous

(IV)

Time (hours)

Rel

ativ

e co

ncen

trat

ion

of d

rug

in b

lood

Clinical Considerations in Prescribing Antimicrobial Drugs

• Safety and Side Effects– Toxicity

• Cause of many adverse reactions poorly understood• Drugs may be toxic to kidneys, liver, or nerves• Consideration needed when prescribing drugs to

pregnant women– Allergies

• Allergic reactions are rare but may be life threatening• Anaphylactic shock

Figure 10.14 Some side effects resulting from toxicity of antimicrobial agents-overview

Black hairy tongue caused by antiprotozoan drug metronidazole (Flagyl)Temporary and Harmless!

Discoloration and damage to tooth enamel caused by tetracycline

Resistance to Antimicrobial Drugs

• The Development of Resistance in Populations• Some pathogens are naturally resistant • Resistance by bacteria acquired in two

ways• New mutations of chromosomal genes• Acquisition of R-plasmids via

transformation, transduction, and conjugation

Antibiotic Resistance

• Misuse of antibiotics selects for resistance mutants

• Misuse includes:– –

– – –

Clinical Focus Antibiotics in Animal Feed Linked to Human Disease, Figure A.

Resistance plasmid

E. c

oli

S. e

nter

ica

S. e

nter

ica

afte

r con

juga

tion

Cephalosporin-resistance in E. coli transferred by conjugation to Salmonella enterica in the intestinal tracts of turkeys.

Antibiotic Resistance– At least 6 mechanisms of microbial resistance

1. 2. 3. 4. 5.

6.

Effects of Combinations of Drugs

• __________occurs when the effect of two drugs together is greater than the effect of either alone

• ___________occurs when the effect of two drugs together is less than the effect of either alone

Figure 20.23 An example of synergism between two different antibiotics.

Disk with antibiotic amoxicillin-clavulanic acid

Disk with antibiotic aztreonam

Area of synergistic inhibition, clear

Area of growth, cloudy