Timmins Protein Synthesis ALL

Question 1

How does Aminoglycosides drive ototoxicity?

Answer 1

The ribosome, the complex that manufactures proteins using instructions from mRNA is different between Bacteria (70 S) and Eukaryotes (80 S).

However, remember, mitochondria derived from bacterial endosymbionts, so have 70 S ribosome. Hence, hosts can be sensitive to mitochondrial damage (drives ototoxicity).

Question 2

Aminoglycosides
All contain amino-substituted inositol derivatives. ie aminosugars
They all bind to the 30 S subunit and . . .

Answer 2

1. Inhibit initiation of translation, bacteria is unable to produce proteins at all
2. Cause misreading of mRNA, producing inactive or unstable proteins. For example, introduction of a polar group in the hydrophobic interior of a protein. Cell then has to degrade these (in a specific proteolytic complex, the proteasome), and resynthesize active ones, very costly in energy terms…
   Recent evidence this induces ROS

Question 3

Aminoglycosides–> Kanamycin (chairs compound attached to each other) . . . how is it inhibited

Answer 3

Produced by fermentation of Streptomyces kanamycetus. Actually is a mixture of different very similar compounds, all with antibacterial activity.

Exceptional chemical and thermal stability, glycosidic bonds quite strong, resistant to hydrolysis. however, like all aminoglycosides it is readily inhibited by R-factor
enzymatic modification at functional groups. Usually acetylation at
amine (NH2) and either adenylation or phosphorylation at hydroxyls (OH).

Modification of aminoglycosides weakens their binding to the bacterial ribosome by multiple routes!!!!!!!!!!!! –. how aminoglycosides get inhibited
(Big bulky group limits ribosome binding via addition of things and Weaker hydrogen bond interaction with ribosome)

Question 4

Macrolides . . MOA and general structure

Answer 4

These inhibit protein synthesis by inhibiting translocation of the amino-acyl tRNA molecules after binding to the 50S subunit.

All US-used macrolides comprise a 14-membered cyclic ester (lactone, remember cyclic amide is a lactam) that is heavily substituted with oxygen (ketones & hydroxyls). Two hydroxyls are further substituted with a sugar, and aminosugar moiety

Question 5

Macrolides (Erythromycin) AND ACID

Answer 5

LOOK AT YOUR NOTE CARD FOR THIS INFORMATION!!!!

Question 6

macrolide: Fidaxomicin oral med!

Answer 6

APPROVED IN 2011 FOR C.DIFF!!!

No oral absorption, selective C. difficile killing
Many more hydroxyls 7, unsaturated macrolide

Question 7

Lincosaminides: Clindamycin general info/ MOA and structure

Answer 7

Contain characteristic thiomethyl aminooctoside, amide linked to an N-methyl pyrrolydiylcarboxylic acid derivative.

Binds to 50 S ribosomal subunit, at similar site
to the macrolides. Cross-resistance common.
Useful in orthopod surgery, as concentrates well
in bones. Heavily associated C diff.

CLINDAMYCIN CAN CAUSE C DIFF

Question 8

Tetracyclins . . . MOA and general chemistry

Answer 8

1. Contain four fused six-membered ring system, different
   Substitutions on tops of left 3 rings B, C, & D provide range of compounds (order in A, B, C, D)
2. Action on 30 S ribosomal subunit, inhibit addition to protein chain.
3. Orally given, but also polymer-based periodontal
   delivery.

Question 9

Tetracyclins and polyvalent cation??

Answer 9

Major structural feature of tetracyclins is their binding to
polyvalent cations, such as Al3+ Ca2+ as quinolones.
Enolization on the ‘bottom’ of the molecule is extensive

Complex has greatly decreased solubility, if formed in GI leads to fecal excretion instead of absorption

Question 10

Tetracyclins Stoichiometry
2 Tetracyclins + Mn 2 = Tet-M(n-2)+ + 2H+
What will be final charge on metal ion in a 2-tet complex for Al3+??

Answer 10

+1 !

This is because equation is n-2 . . . so Al3 - 2 = 1

Question 11

Tetracyclins

Leads to two major effects

Answer 11

insolubility of chelate, leads to incomplete absorption!!!!!
Counsel re Ca2+, Fe2/3+, Al3+

However, they also have a great affinity for Ca2+ in the
teeth, and are precipitated in forming teeth & bones,
leading to yellow discoloration & even weakening.
Hence kids forming permanent adult teeth (6 up to ~12)
shouldn’t be given these compounds

Question 12

NEW Tetracycline agent . . . Tigecyclin

Answer 12

New agents have more amines (“N”), a bit of lipophilicity, greater t1/2.
• Tigecyclin- t1/2 >24 hours (higher in multidose)
• Not acted upon by tet-like efflux pumps, able to overcome some resistance.

Question 13

• Tigecyclin- Log p = 0, acceptors 13, donors 8 –

dosage route?

Answer 13

IV/ Peritoneal !!! Poor oral absorption

Question 14

Tetracyclins can cause local skin damage . . . HOW??

Answer 14

Very flat, large & rigid 4 ring structure. Very good at absorbing UV light, but cannot lose energy by ‘wobbling” (as heat) as most drugs can

This absorbed energy causes production of: Singlet oxygen, an excited form of O2, local skin damage

Drug based radicals – local damage and potential immunotox

Question 15

Oxazolidones

Drugs and MOA??
Coverage?

Answer 15

MOA: – MOA Protein synthesis inhib @ 50S

DRUGS: Linezolid and Tedizolid

Coverage V similar to vancomycin and lipoglycopeptide/ lipopeptide !! Covers gram +: MRSA, MSSA, and S. Pneumonia

Question 16

Oxazolidines- Linezolid

MOA, PK Prop . . .oral or iv? disadvantage/ AE?

Answer 16

Mechanism: Binds 50S at unique site. Cross resistance rare to never.

PK Properties: Log P = 0.7 H acceptor 7 H donor 1.
Bioavailability = almost 100% Protein binding ~ 30%
However poor aqueous solubility only 3 mg / ml (IV premixed at 2mg/ml) so poor
for IV use.

Disadvantages Cost. Now available generic
Neuropathy in extended treatment.

Question 17

Newest oxazolidone Tedizolid

Talk about structure

Answer 17

Prodrug, 91% oral bioavailable. Allows switch from IV. 1x daily

Tedizolid (prodrug) has a phosphate group! phosphatases cleaves that off to activate the drug

Question 18

Why is tedizolid given as disodium salt of phosphate prodrug??

Answer 18

To increase water solubility of IV form

Question 19

Why is tedizolid good for treating MRSA pneumonia??

Answer 19

Tedizolid is strongly concentrated in lung ELF (epithelial lining fluid)