Tetracyclines (MC) - Block 2

Question 1

What is the SAR of tetracyclines?

Answer 1

Redced naphthacene ring (4 linearly fused 6 membered rings)
* Binding face is on the bottom (with the oxygens)
* 3 pKa (2 acidic hydroxyls, 1 basic amine)

Question 2

Tetracycline resistance is due to?

Answer 2

Mutation of ribosomal proteins that allow binding of aminoacyl-tRNA in the presence of tetras

Question 3

What are the ADRs of tetracyclines?

Answer 3

1. Phototoxicity
2. Bne weakness
3. Tooth discoloration
   * Ca2+ bind to tetra binding sites

Question 4

MOA of tetracycline?

Answer 4

Formation of an incomplete protein (inhibits protein synthesis) by binding to 30S ribosomal subunit prevetning tRNA binding

Question 5

What is the antimicrobial activty of tetras?

Answer 5

Bacteriostatic:
* Not used in peds due to tooth discoloration

Question 6

What are the ADRs of high doss of tetracyclines?

Answer 6

Imperfect distinction between the bacterial 70S and mammalian 80S rbosomes -> antianabolic effect and severe liver/kidney damae

Question 7

What are terta resistance enzymes?

Answer 7

TetM, TetO

Question 8

What is TetM?

Answer 8

Produces proteins capable of displacing tetracyclines from ribosomes

Question 9

What is TetO?

Answer 9

• Protein capable of pumping tetracyclines out of cells by increasig efflux channels

Question 10

Describe tetracyclines’ response to stong and weak acids?

Answer 10

Mild acid: epirimization will flip the molecule at C4 and inactivate the drug
Strong acid: OH as an R group can dehyrdate the molecule -> inactivation and renal toxic

Question 11

Describe tetracycline’s response to bases?

Answer 11

Hydrolysis ring C, 6-OH will attack opening up the ring -> H2O will leave and lactone metabolite is formed -> Inactive drugs

Question 12

Describe tetracyclines relationship with metals?

Answer 12

Ca2+, Mg2+, Fe2+ and 3+, Al3+: will chelate the binding sites of tetracycline (e.g. precipitation)
* Chelaton before absorption -> decreased drug uptake

Question 13

When are tetracyclines more likely to be dehydrated?

Answer 13

When R3 is OH and R2 is a methyl

Question 14

What tetracyclines aren’t toxic in the present of acids? WhY?

Answer 14

Doxycyline, Minocycline, and Methacycline do not contain OH on R3 and CH2 on R2 -> less susceptible to be dehydrated

Question 15

Describe the binding site of tetracyclines?

Answer 15

Binds to rRNA (16S) A site -> prevents binding of amniacylated tRNA
* Mg2+ bridge binding (binding to O drug and chelate phosphates on residues)

Question 16

Spectrum of activity of tetras?

Answer 16

1. G+ and -
2. Atypicals
3. Protozoa

Question 17

What is the biggest offender of phototox in tetras?

Answer 17

Cl on D ring

Demeclocycline

Question 18

Describe the characterisitcs of this tetra structure?

Answer 18

1. No Cl on D ring -> low phototox
2. Tert OH and methyl -> dehydration

Oxytetracycline

Question 19

Describe the characterisitcs of this tetra structure?

Answer 19

1. Cl -> phototox
2. Secodnary alcohol provides more stability against dehydration

Demeclocycline

Question 20

Describe the characterisitcs of this tetra structure?

Answer 20

1. No 6-OH -> no dehydration
2. 7-dimethyl amine reduces acidity of 10-OH -> more stable basic environements

Minocycline

Question 21

What is function of the R group on the left of minocycline?

Answer 21

Tigecycline: glycyl chain gives activity against resistant strains

Question 22

Types of tetras?

Answer 22

1. Doxyclycline
2. Minocycline
3. Tigecyline
4. Oxytetacycline
5. Demeclocycline