*Chemotherapeutic Antibiotics: Protein Synthesis

Question 1

Protein synthesis reminder

Answer 1

In the bacterial cell the structures devoted to protein synthesis are ribosomes
Each ribosome is made of 2 parts, and each part in turn is made of two different kinds of macromolecules: ribosomal protein and ribosomal RNA
70S ribosome made of 30S and 50S

Question 2

Protein synthesis inhibition

Answer 2

Selective inhibition of bacterial protein synthesis by interference with functions of the 70S ribosome yields many antibiotics- macrolides, tetracyclines, AGACs, chloramphenicol and oxazolidinone
The majority of existing inhibitors bind to the 16S or 23S rRNA components of the ribosome
3D structure of inhibitor and ribosome important

Question 3

Tetracyclines

Answer 3

Binds to a single site in the 30S ribosomal subunit
Involves a region of 16S ribosomal RNA which contains base 892, tRNA anti-codon is spatially proximal to the 16S RNA base region containing base 1400
Tertiary folding of the ribosomal RNA brings 892 and 1400 region in close proximity- antibiotics interfere with tRNA binding

Question 4

Tetracycline indications

Answer 4

Tetracycline- broad spectrum, chlamydia
Doxycycline- anthrax
Minocycline- meningococcal carrier state, acne
Tigecycline- MRSA, VRE
Doxycycline also used for pneumonia where there is a penicillin allergy

Question 5

Macrolides

Answer 5

Macrolides selectively inhibit protein synthesis by binding to the 50S subunit- selectively bind to a single high affinity site, do not bind to mammalian 80S ribosomes
Bind directly to 23S ribosomal RNA in 2058-2062 nucleotide region of the molecule, dislodges tRNA from binding site
Macrolides block translocation, causing the release of incomplete polypeptides from the ribosome

Question 6

Macrolide indications

Answer 6

Erythromycin- penicillin hypersensitivity, oral infections, RTI, skin infections, STIs
Azithromycin- RTI, otitis media, skin and soft tissue infections, chlamydia, prophylaxis of s. aureus infections
Clarithromycin- RTI, otitis media, mild to moderate skin and soft tissue infections, H pylori eradication

Question 7

Lincosamides

Answer 7

Clindamycin
Bacteriostatic action- inhibits microorganism, does not kill it quickly so important that patient finishes course
Binds to 50S ribosomal subunit, similarly to macrolides and inhibit early stage of protein synthesis

Question 8

Indications of clindamycin

Answer 8

Gram positive cocci, penicillin resistant staphylococci, staphylococcal joint and bone infections, osteomyelitis, intra-abdominal sepsis, MRSA

Question 9

Streptogramins

Answer 9

Quinupristin/Dalfopristin
Bacteriostatic when used individually but bactericidal when used together
Interfere with protein synthesis by binding to the 50S ribosomal subunit

Question 10

Streptogramin indications

Answer 10

Serious gram positive infections, HA pneumonia, skin and soft tissue infections, VRE, MRSA

Question 11

Aminoglycosides

Answer 11

Bactericidal activity against some gram positive and many gram negative bacteria
Gentamicin- binds irreversibly to 30S ribosomal subunit, stop translocation and stop protein synthesis, may also generate errors in the translation of the genetic code and affect bacterial membrane permeability
Spectinomycin- binds to the 30S subunit and inhibits protein synthesis

Question 12

Aminoglycoside indications

Answer 12

Gentamicin- Ps aeruginosa, serious infections, broad spectrum, sepsis, meningitis, CNS infections, biliary tract infection, endocarditis, HA pneumonia
Amikacin- Ps aeruginosa, gentamicin resistant gram negative bacilli
Streptomycin- M tuberculosis
Tobramycin- Ps aeruginosa, cystic fibrosis

Question 13

Chloramphenicol

Answer 13

Bacteriostatic action
Binds 50S ribosomal subunit and prevents attachment of tRNA to its acceptor site, preventing peptide bond formation
Might competitively inhibit the effect of macrolides and lincosamides- don’t use together

Question 14

Chloramphenicol indications

Answer 14

Broad spectrum, eye/ear drop, treatment of life threatening infection, H influenza

Question 15

Fusidic acid

Answer 15

Apart from rRNA, other components of the translation machinery could serve as targets for new drugs- the initiation factor and elongation factor
Fusidic acid inhibits protein synthesis by inhibiting the factor necessary from translocation of peptide subunits and elongation of the peptide chain

Question 16

Fusidic acid indications

Answer 16

Osteomyelitis, endocarditis

Question 17

Mupirocin

Answer 17

Prior to incorporation into polypeptides, amino acids are attached to specific tRNA molecules
tRNA molecules are linearly ordered by interacting with mRNA bound in the ribosome
Mupirocin inhibits bacterial isoleucyl tRNA synthetase
Used for MRSA only

Question 18

Linezolid

Answer 18

Oxazolidinone
Appears to block early stage of protein production
Indications: MRSA, VRE, pneumonia, complicated skin and soft tissue infection caused by gram positive bacteria