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Antimicrobials 1: Origins and modes of action. Dr Fiona Walsh. Objectives of lecture. Antibiotic discovery Time-line of currently prescribed antibiotics General principles of antimicrobial agents How antibiotics inhibit or kill bacteria Introduction to all antibiotic classes. Definitions.

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objectives of lecture
Objectives of lecture
  • Antibiotic discovery
  • Time-line of currently prescribed antibiotics
  • General principles of antimicrobial agents
  • How antibiotics inhibit or kill bacteria
  • Introduction to all antibiotic classes
definitions
Definitions
  • Antibiotic is a naturally occurring substance that inhibits or kills bacteria
  • Antibacterial is a natural, semi-synthetic or synthetic substance that inhibits bacteria
  • Antimicrobial agent is a natural, semi-synthetic or synthetic substance that inhibits microbes
antibiotic discovery
Antibiotic discovery

19th Century

Louis Pasteur Identified bacteria as causative agent of

Robert Koch disease. (Germ theory)

Now know what is causing disease, need to find out how to stop it.

1877 Pasteur Soil bacteria injected into animals made Anthrax harmless

1888 de Freudenreich Isolated product from bacteria with antibacterial properties. Toxic and unstable.

antibiotic discovery1
Antibiotic discovery

20th Century

Erhlich Worked with dyes and arsenicals worked against Trypanosomes, very toxic.

1st antibacterial, only cured syphilis.

Domagk Research on dyes.

1st synthetic antibacterial in clinical use. Prontosil cured streptococcus diseases in animals.

Active component: sulphonamide group attached to dye.

Toxic.

Sulphonamide derivatives still used.

Less toxic.

antibiotic discovery2
Antibiotic discovery

20th Century

Fleming and Plates left on bench over weekend.

serendipity (1928) Staphylococcus colonies lysed/killed.

Fungi beside Staphylococcus.

Hypothesis: Fungi lysed Staph.

Unable to purify in large quantities.

No animal or human tests performed.

antibiotic discovery3
Antibiotic discovery

20th Century

Florey, Chain Purified the penicillin from the fungus.

and Heatley (1939)

1940s (World War II) European and US cooperation led to increased scale production of penicillin.

antibiotic discovery4
Antibiotic discovery

20th century

Waksman (1943) Isolated streptomycin from soil bacteria Streptomyces.

Effective against Mycobacteriumtuberculosis and gram negatives .

Toxic antibiotic. Used until 1950s when isoniazid used due to shorter course of therapy.

general principles
General Principles
  • Selective toxicity
    • The essential property of an antimicrobial drug that equips it for systemic use in treating infections is selective toxicity
    • Drug must inhibit microorganism at lower concentrations than those that produce toxic effects in humans
    • No antibiotic is completely safe
general principles1
General Principles
  • Oral and Parental
    • Oral antibiotics must be able to survive stomach acid
    • Advantage: Ease and reduced cost
    • Disadvantage: Circuitous route, antibiotic passes to lower bowel
    • Parental antibiotics given by i.v.
    • Advantage: Direct route to site of infection
    • Disadvantage: Increased cost and need for qualified staff
general principles2
General Principles
  • Half-Lives
    • The length of time it takes for the activity of the drug to reduce by half
    • Short half lives require frequent dosing
    • Old antibiotics have short half lives
    • New antibiotics may have half lives up to 33 hours
general principles3
General Principles
  • Broad and Narrow spectrum antimicrobials
    • Broad spectrum antibiotics inhibit a wide range of bacteria
    • Narrow spectrum antibiotics inhibit a narrow range of bacteria
    • Broad spectrum desirable if infecting organism not yet identified
    • Narrow spectrum preferable when organism has been identified
general principles4
General Principles
  • Bactericidal or bacteriostatic action
    • Bactericidal antibiotics kill bacteria
    • Bacteriostatic antibiotics inhibit the bacterial growth
    • Bacteriostatic antibiotics may work as well as bactericidal antibiotics if they sufficiently arrest the bacterial growth to enable the immune system to eliminate the bacteria
general principles5
General Principles
  • Combinations of antibiotics
    • Some antibiotics work better together than alone
    • Combining 2 or more drugs may be required to prevent the emergence of resistance e.g. tuberculosis
    • Combinations should not be given when 1 drug would suffice
      • Antagonistic effects
      • No ability to adjust 1 drug concentration
modes of action
Modes of action

Antimicrobial agents inhibit 5 essential

bacterial processes:

  • Protein synthesis
  • Folic acid synthesis
  • DNA synthesis
  • RNA synthesis
  • Cell wall synthesis
protein synthesis inhibitors
Protein synthesis inhibitors

Protein synthesis

DNA mRNA Protein

transcription translation

Ribosome is a protein factory in bacteria takes mRNA in and

produces proteins from them.

Bacterial ribosome has 2 parts:

  • 30S binds to mRNA to translate mRNA into amino acids, which form proteins
  • 50S required for peptide elongation

3 phases from mRNA to protein

  • Initiation
  • Elongation
  • Termination
protein synthesis inhibitors1
Protein synthesis inhibitors
  • Aminoglycosides
  • Macrolides/Ketolides
  • Tetracyclines
  • Lincomycins
  • Chloramphenicol
  • Oxazolidinones
protein synthesis inhibitors2
Protein synthesis inhibitors
  • Bind irreversibly to ribosome
  • Ribosome cannot bind to mRNA to form amino acid chains (30S) or elongate the chains to form proteins (50S)
  • Disruptive effect on many essential bacterial functions leading to cell death
2 folic acid synthesis inhibitors
2. Folic acid synthesis inhibitors

pterdine + para-amino benzoic acid

dihydropterate

dihydrofolate

tetrahydrofolate

DNA/RNA

Sulphamethoxazole

(Sulphonamides)

Structural analogues of PABA

Dihydropteroate synthetase

Dihydrofolate reductase

Trimethoprim

(Diaminopyrimidines)

Binding

reasons for combining trimethoprim and sulphonamides
Reasons for combining Trimethoprim and Sulphonamides
  • There is synergy between the two drugs - the combined effect is greater that the expected sum of their activities
  • Individually the drugs are bacteriostatic; however, in combination they are bactericidal
  • The use of two drugs will delay the emergence of resistance
3 dna synthesis inhibitors
3. DNA synthesis inhibitors
  • Enzymes required for DNA replication
  • Topoisomerase II (DNA gyrase): GyrA and GyrB
  • Topoisomerase IV: ParC and ParE
  • Quinolones interact/bind to the topoisomerases, which stops DNA replication e.g. nalidixic acid, ciprofloxacin
action of fluoroquinolones
Action of fluoroquinolones

GyrA/GyrB

DNA gyrase

DNA

ParC/ParE

Topoisomerase IV

Quinolones

Cell death

dna synthesis inhibitors
DNA synthesis inhibitors
  • Metronidazole
    • Nitro group is reduced by bacterial enzyme
    • Produces short-lived, highly cytotoxic free radicals that disrupt the DNA
    • Similar effect to UV radiation on cell DNA
4 rna synthesis inhibitors
4. RNA synthesis inhibitors
  • Rifampicin
  • Forms a stable complex with bacterial DNA-dependent RNA polymerase
  • Prevents chain initiation process of DNA transcription
  • Mammalian RNA synthesis not affected as RNA polymerase is much less sensitive to rifampicin
5 cell wall synthesis inhibitors
5. Cell wall synthesis inhibitors
  • Vancomycin
  • Bacitracin
  • β-lactams
    • Penicillins
    • Cephalosporins
    • Carbapenems
    • Monobactams
  • β-lactamase inhibitors
    • Clavulanic acid
    • Sulbactam
    • Tazobactam
action of cell wall synthesis inhibitors

NAMA

L-ala-D-glu-L-lys

NAMA

L-ala-D-glu-L-lys-D-ala-D-ala

Action of Cell wall synthesis inhibitors

N-acetyl-glucosamine (NAG)

Phospho-enol pyruvate

Peptidoglycan formation

1. Building Blocks

N-acetyl-muramic acid (NAMA)

L-alanine

D-glutamic acid

L-lysine

D-ala-D-ala

D-ala

L-ala

action of cell wall synthesis inhibitors1

NAMA

L-ala-D-glu-L-lys-D-ala-D-ala

NAMA - NAG

NAMA - NAG

L-ala-D-glu-L-lys-D-ala-D-ala

L-ala-D-glu-L-lys-D-ala-D-ala

Action of Cell wall synthesis inhibitors

Lipid

carrier

NAG

Bacitracin inhibits

5 gly

Vancomycin &Teicoplanin binds, prevents enzyme polymerisation

Phospholipid

5 gly

action of cell wall synthesis inhibitors2

NAG

NAG

NAG

NAG

NAG

NAMA

NAMA

NAMA

NAMA

NAMA

L-ala

L-ala

L-ala

L-ala

L-ala

D-glu

D-glu

D-glu

D-glu

D-glu

L-lys

L-lys

L-lys

L-lys

L-lys

5 gly

5 gly

5 gly

5 gly

5 gly

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

Action of Cell wall synthesis inhibitors

Polymerisation

action of cell wall synthesis inhibitors3

NAG

NAMA

NAG

NAMA

NAG

NAMA

L-ala

D-glu

L-ala

L-ala

D-glu

D-glu

L-lys

5 gly

D-ala

L-lys

L-lys

5 gly

5 gly

D-ala

D-ala

D-ala

D-ala

D-ala

Action of Cell wall synthesis inhibitors

Transpeptidation

b-lactams resemble D-ala-D-ala, bind to enzyme, inhibit cross-linking

D-ala

D-ala

D-ala

D-ala

D-ala

D-ala

L-lys

L-lys

L-lys

D-glu

D-glu

D-glu

L-ala

L-ala

L-ala

NAMA

NAG

NAMA

NAG

NAMA

NAG

slide31

Penicillin Binding Proteins

Enzymes involved in cell wall formation

  • Reseal cell as new peptidoglycan layers added
  • Penicillins bind to PBPs block enzyme cross-linking chains
  • Weak cell wall
  • Build up osmotic pressure
  • Lysis
keynote points
Keynote points
  • Recent history of antibiotic discovery
  • General principles of antibiotic action
  • 5 modes of action
  • Examples of each