Molecular bacteriology of infectious diseases (2066FBDBMW)
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Universiteit Antwerpen (UA)
This document includes all of the information/course material of the course Molecular bacteriology of infectious diseases. It contains all of the topics that have been discussed in class. Part of the Master's degree: Biomedical Sciences: Infectious and Tropical Diseases of Uantwerpen.
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Molecular bacteriology of infectious diseases (2066FBDBMW)
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Molecular bacteriology
Exam: written examen with mcq (15%) and 3-4 open questions (50%)
Also a paper presentation (20%) + practicals (15%) and demonstrations
1. NEW ANTIBIOTICS CLASSIFICATION
An AB = a drug that kills bacteria (bactericidal) or prevents multiplication of bacteria (bacteriostatic).
The specificity of an antibiotic resides in its ability to damage the bacteria and not the host. 1928: The
first antibiotic, penicillin, was discovered by Alexander Fleming.
The targets need to be different from eukaryotic pathways so they don’t damage the host.
Classification of antibiotics based on the target site:
1. Metabolic analogues 4. Cell wall inhibitors
2. Protein synthesis inhibitors 5. DNA inhibitors
3. Cell membrane inhibitors
1. METABOLIC ANALOGUES
Antibiotics that function by mimicking some metabolite or molecule that is required by the
bacteria, but is not required by the host. In this case, this is the folic acid pathway. We get folic
acid from e.g. green vegetables and can’t make it ourselves. Bacteria can synthesize it out of
PABA: para-aminobenzoic acid. Certain drugs mimic PABA: structural analogues.
1. Sulphonamides 2. Trimethoprim
These two are usually given together because they work synergistically because they target different
steps of the same pathways. They are both structural analogues. The combination of the two is known
as co-trimoxazole and works very well. This is very commonly used in Africa.
Dapsone is an AB that targets mycobacterium leprae. It is also a metabolic analogue.
2. PROTEIN SYNTHESIS INHIBITORS
Protein synthesis is different in bacteria than in man so it’s a good target for AB. The bacterial ribosome
is 70S, with a large ribosomal unit (50S) and a small unit (30S). They both have important active centers:
IPE and mRNA binding site and its own dominant rRNA. This is not transcribed but thrown into domains
which make up the ribosome. For the big subunit: 23S rRNA (major binding site for AB), for the small
unit: 16S rRNA (used to identify bacteria, highly conserved area. Very specific for each species).
The active centers are where protein synthesis happens and the ribosome binds. The ribosome binds
to the mRNA. Transcription and translation happen at the same time because mRNA in bacteria is very
unstable. You have formation of the initiation complex around the AUG codon in the P-site.
- A site: entry site for tRNA
- P-site: occupied by peptidyl tRNA: carries the growing polypeptide chain
- E-site: exit site for tRNA when it’s done delivering AA
, https://youtu.be/KZBljAM6B1s
A new tRNA carrying an AA enters the A-site of the ribosome. Here, the anti-codon of the incoming
tRNA is matched to the mRNA codon in the A-site. A peptide bond is made between the AA on the P-
site and on the A-site. The tRNA in the P-site releases the AA on the tRNA in the A-site and becomes
empty. The ribosome moves one triplet further on the mRNA. The A-site is ready to accept a new tRNA.
When a stopcodon is positioned in the A-site, no tRNA can fit in the A-site. The codon is recognized by
the release factor which binds and calayzes the binding between the polypeptide and the tRNA. The
polypeptide is released through a tunnel and the ribosome is disassociated into subunits -> repeat.
PROTEIN SYNTHESIS INHIBITORS
- Tetracyclines: bind to the 30S subunit and prevent attachment of amino-acyl tRNA to A-site
- Aminoglycosides: bind to 30S subunit at A site
o Inhibits peptide chain transfer
o Interferes with formation of the initiation complex
- Mupirocin: binds to bacterial isoleucyl tRNA synthetase
o Halts incorporation of isoleucine into peptide chain
o It stops protein synthesises if a isoleucine is required
- MASK: see later
- Fenicole: binds to 50S and prevents ribosomal translocation & inhibits peptide bond formation
- Lincosamides: bind to 50S and inhibits transpeptidase and peptide chain elongation
- Fusidic acid: binds & inhibits peptide chain elongation factors: prevents elongation
EXAMPLES OF DIFFERENT PROTEIN SYNTHESIS INHIBITOR AB
- Lincosamides
Lincosamides, macrolides and streptogramins
1) Lincomycin 2) Clindamycin all have a common binding site on 50S
-> macrolide resistance will also give
- MASK resistance to the other two groups because
1) Macrolides: includes azalides and ketolides the binding sites are so close to each other
i. 14 ketones: erythromycin & clarithromycin
ii. 15 ketones: azithromycine
iii. 16 ketones: josamycine & spiramycine
2) Azalides: azithromycin
3) Ketolides: telithromycin
4) Streptogramins
Phospholipid bilayer with hydrophilic heads of the phospholipids to the outside and hydrophobic tails
to the inside of the bilayer (amphiphilic molecules). There are many protein channels which prevent
entry of molecules and only allows some transport.
CELL MEMBRANE INHIBITORS
- Polymyxins: alters the permeability of the cell membrane (toxic)
A. Colistin B. Polymyxin B
4. CELL WALL INHIBITORS
G- bacteria:
- Outside: possible capsule Outer lipid membrane with virulent factors (Ag) and porins
- Thin peptidoglycan
- Inner side: plasma membrane
➔ Not every AB can pass through the porins
G+ bacteria:
- Outside: possible capsule No outer membrane
- Thick peptidoglycan cell wall: different layers
o Lipoteichoic acid ‘pilars’
- Inner side: plasma membrane
➔ AB can come in through passive diffusion (easier than G-)
Gram-staining: you apply crystal violet which colors G- AND G+ purple, and do a rapid decolorization
with alcohol, which in the case of G- removes the purple color, and counterstain with safranin which
makes G- become pink. G+ have thick cell walls with 90% peptidoglycan: purple color stays.
, The structure of peptidoglycan
Peptidoglycan is made up of NAG-NAM sugars. And to each of the NAMs a peptide chain is attached.
(NAG: N-acetylglucosamine, NAM: N-acetyl muramic acid). 2 binds make the peptidoglycan strong:
- Stacked layers of NAG-NAM sugars with glycosidic bonds between NAG and NAM
o = transglycosylation
- NAMs have peptide chains forming a penta-peptide bridge: crosslinking
o = transpeptidation
PBPs are bifunctional enzymes and carry out both reactions.
CELL WALL INHIBITORS
- Glycopeptides: vancomycin & teicoplanin
- Cycloserine
- B-lactams: binds to PBPs and inhibit transpeptidation
o Penicillins
o Cephalosporins: 4 generation (first against G+, last against G-)
o Monobactams: aztreonam
o Carbapenems: imipenem & meropenem
- Bacitracin: interferes with a molecule which carries the building blocks of peptidoglycan
Mechanism of action of vancomycin
Vancomycin binds to D-Ala-D-Ala and prevents transpeptidation.
This is a physical blockage. The difference with B-lactams is that B-
lactams bind to the enzyme. Essentially both weaken the
peptidoglycan.
Different kinds of penicillins
- Small spectre penicillins: penicillin
- Broad spectre penicillins: amoxicillin, ticarcillin, piperacillin
- Combination with B-lactams: amoxi-clav, ticar-clac, pipera-lazobactam
o Molecules which bind to the enzyme and keep it bound
- Penicillinase-resistant penicillins: cloxacillin, flucloxacillin
5. DNA INHIBITORS
1. Inhibiting transcription
1) Rifampicins E.g. Rifampicin and refabutin
2. Inhibiting replication
1) 5-nitro-imidazoles E.g. Metronidazole, tinidazole, ornidazole
2) Quinolones: form complex w/ DNA polymerase & enzyme which changes DNA topology
i. First gen. E.g. norfloxacine
ii. Second gen. E.g. ofloxacine, pefloxacine, ciprofloxacine
iii. Third gen. E.g. moxifloxacin
Rifampicins form a stable drug-enzyme complex with RNA polymerase, and stop DNA transcription.
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