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Chemotherapy BMSC2210 > Lecture 7 Antibacterial drugs targeting protein synthesis > Flashcards

Lecture 7 Antibacterial drugs targeting protein synthesis Flashcards

1
Q

Name an example of a pre-ribosomal stage inhibitor

A

Mupirocin

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2
Q

Name examples of a early stage protein synthesis inhibitor

A

linezolid

tertracyclines

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3
Q

Name examples of mid stage protein synthesis inhibitors

A

aminoglycosides
chloramphenicol
macrolids

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4
Q

Name an example of a late stage protein synthesis inhibitor

A

fusidic acid

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5
Q

What are the 3 stages of translation?

A

1) Initiation
2) Elongation cycle
3) Termination

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6
Q

Describe the elongation stage of translation.

A

1) AUG tRNA binds to the P site.
2) The A site will be the “landing site” for the next tRNA, one whose anticodon is complementary to the exposed codon.
3) Once the matching tRNA has landed in the A site, a peptide bond is formed between the 2 AAs.
4) Once the peptide bond is formed, the mRNA is pulled onward through the ribosome and AUG moves to the E site and leaves the ribosome. It also exposes a new codon in the A site, so the whole cycle can repeat.

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7
Q

Why is targeting ribosomes selectively toxic to bacteria?

A

Differences in human and bacterial ribosomes

Bacterial ribosomes are smaller and made from different RNA

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8
Q

What makes mupirocin selectively toxic?

A

Structural differences between eukaryotic and prokaryotic isoleucyl-tRNA synthetase

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9
Q

What makes fusidic acid and tetracycline selectively toxic?

A

differences in uptake of antibiotic into eukaryotic and prokaryotic cells - preferential to bacteria

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10
Q

What is meant by ‘mechanism-based toxicity’ and how does this occur with ribosome inhibitors?

A

Side effect due to the mechanism of action of the drug.

Due to inhibition of mitochondrial protein synthesis which shares similarities with bacterial protein synthesis.

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11
Q

Describe the spectrum of mupirocin

A

Narrow spectrum

Gram +ve

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12
Q

Describe the mechanism of action of mupirocin

A

Bacteriostatic
Natural product antibiotic
Acts as a substrate analog to inhibit isoleucyl tRNA synthetase
Does not interfere with the ribosome directly
Isoleucine cannot be incorporated into the chain = inhibition of protein synthesis
Works as a competitive inhibitor that is 8000x more potent

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13
Q

In what form is mupirocin given?

A

Topically
Not applied systemically due to rapid de-esterification in kidney and liver = producing metabolites lacking antibiotic activity.
Due to topical treatment, it is well tolerated

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14
Q

What bacteria are sensitive to mupirocin?

A

staphylococcal and streptococcal skin infections

nasal carriage of MRSA

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15
Q

Which antibiotics target specifically the 50s subunit?

A 
Macrolids
Lincosamides
Streptogramins
Oxazolidinones
Aminoglycosides (and also 30s)
Chloramphenicol
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16
Q

Which antibiotics target specifically the 30s subunit?

A

Aminoglycosides (and also 50s)

Tetracyclines

17
Q

Name an example of an antibiotic in the oxazolidinone class and its spectrum of action

A

Linezolid and Tedizolid (2014)

gram +ve due to being removed by efflux in gram -ve’s

18
Q

Describe the mechanism of action of the oxazolidinone class

A

Only fully synthetic drug to target RNA
Binds to the 50s subunit at the site where it normally interacts with the 30s subunit = full subunit not formed.
Structural studies with LZD have revealed that the drug interferes with binding or correct positioning of aminoacyl-tRNA in the ribosomal A site

19
Q

What is linezolid used for?

A

oral/iv agents for the treatment of Gram+ve infections

Treatment of pneumonia or skin/soft tissue infections

20
Q

What are the side effects of linezolid?

A

Skin reactions e.g. rashes, dermatitis
GI e.g. vomiting
Abnormalities in liver function
Reversible thrombocytopenia and anemia (mechanism-based toxicity)

21
Q

Why is Tedizolid and improvement to linezolid?

A

Reduced risk of myelosupression

Increased bacterial potency

22
Q

Describe the spectrum of tetracyclines

A

Broad

Lipophilic members e.g. doxycycline more active than hydrophobic members e.g. tetracycline

23
Q

Describe the mechanism of action of tetracyclines

A

Bind to 30s subunit
Prevents the association of aminoacyl-tRNA with the ribosomes (same as oxazolidinone but binds to a different subunit)
Tigecycline (3rd generation) developed and marketed which solves resistance problems to earlier TETs

24
Q

What are the clinical uses for tetracyclines?

A

Mostly given orally

Skin, soft tissue, and intra-abdominal infections

25
Q

What are the adverse effect of tetracyclines?

A

GI disturbances - for oral products
Photosensitivity
CNS effects - mainly for minocycline
Deposition in developing teeth and bones - due to collation of metal ions - therefore contraindicated for young children/late in pregnancy

26
Q

What is the mechanism of action of aminoglycosides?

A

Most bactericidal
Either binds to 30s (streptomycin, spectinomycin) or both 30s and 50s subunits (kanamycin, tobramycin)
Effects the proof reading by causing a mis-read of mRNA = production of abnormally folded proteins
Insertion of abnormal proteins into the cytoplasmic membrane = membrane destabilisation and bacterial cell death

27
Q

What are the clinical uses of aminoglycosides?

A

Mostly given IV/IM
Serious gram -ve infections mostly

Given alone for:
Severe sepsis caused by Enterobacteriaceae and Ps.aeruginosa
Plague and tularemia
Enterococcal endocarditis

Used in combo for:
Gram +ve and anaerobic infections
TB

28
Q

What are the adverse side effects of aminoglycosides?

A

Toxicity - dependent on the specific aminoglycoside
Ototoxicity - effects on vestibular and cochlear branches of the 8th nerve and destruction of inner hair cells, effects up to 10% of patients
Nephrotoxicity
Neuromuscular blockade

29
Q

What is the mechanism of action of chloramphenicol?

A

Broad spectrum
Binds to 50s subunit
Inhibits peptidyl transferase activity = stops peptide bond formation

30
Q

What are the clinical uses of chloramphenicol?

A

Clinical use restricted due to toxicity

Still has a role in the treatment of typhoid and paratyphoid fever caused by salmonella

31
Q

What are the adverse effects from chloramphenicol?

A 
Bone marrow depression - can lead to aplastic anaemia , probably from inhibition of protein synthesis in human marrow cell mitochondria
Grey syndrome (infants and babies) - due to build up of the drug, life threatening and presents as cyanosis ('grey skin'), abdominal distention, vomiting and circulatory collapse
32
Q

Name one of the worlds best selling macrolid

A

Azithromycin

33
Q

Describe the clinical use of azithromycin

A

Chlamydia

Respiratory infections - e.g. haemophilus influenzae, moraxella catarrhalis

34
Q

What is the mode of action of macrolids?

A

Binds to the 23s rRNA at the peptide exit site in the 50s subunit exit tunnel of the nascent chain = chain cannot leave the ribosome and protein cannot be made (premature dissociation of the peptidyl-tRNA from the P-site)

35
Q

What adverse effects are associated with macrolids?

A

Generally well tolerated

Can cause GI issues, jaundice and ototoxicity (rare)

36
Q

What is the mechanism of action of fusidic acid?

A

Normally EF-G is an enzyme that catalyzes translocation of tRNA and mRNA down the ribosome at the end of each elongation.
Fusidic acid binds to EF-G and locks in the protein at the translocation stage.
Interfering with the release of elongation factor G from the ribosome.

37
Q

What is the spectrum of activity of fusidic acid?

A

Limited to gram +ve organisms

38
Q

What are the clinical uses of fusidic acid?

A

topical, oral and IV therapy for staphylococcal infections.
Usually administered in combination with other agents to suppress the emergence of point mutations in EF-G conferring resistance.

39
Q

What are the adverse effects caused by fusidic acid?

A

Side effects are rare
Rashes
Jaundice

Chemotherapy BMSC2210 (14 decks)

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