the medicine Flashcards
prokaryotic ribosome size
30s
eukaryotic ribosome size
50s
what are ribosomes responsible for
protein synthesis
Without functional ribosomes, bacteria
cannot survive. This is why ribosomes are
such an important target for new
antibiotics
what are the 4 phases of bacterial protein synthesis
- Initiation
- Elongation (transpeptidation)
- Termination
- Ribosome recycling
describe initiation
Various initiation factors are involved.
* The small ribosomal subunit, typically bound to an
aminoacyl-tRNA containing the first amino acid methionine,
binds to an AUG codon on the mRNA and recruits the large
ribosomal subunit.
* The two subunits to clamp around the mRNA with the
initiator tRNA bound in the ribosomal P-site.
what do Oxazolidinones do?
inhibits initiation
inezolid is a synthetic oxazolidinone antimicrobial drug
* Indicated for gram-positive infections
* Linezolid binds to a site on the bacterial 50S subunit, preventing the formation
of a functional 70S initiation complex.
* Stops protein synthesis
* Linezolid is bacteriocidal against the majority of streptococcal strains and
bacteriostatic against staphylococci and enterococci.
what is transpeptidation, elongation
The amino acid at the P site is transferred to the amino acid
at the A site of the growing polypeptide chain
TRANSPEPTIDATION
describe movement of ribosome from site letters
EPA
describe elongation
- A new aminoacyl-tRNA to binds to the codon in the A site.
- The amino acid at the P site is transferred to the amino acid
at the A site of the growing polypeptide chain -
TRANSPEPTIDATION - The two tRNA units remain bound to the mRNA and the
ribosome moves along by one codon so that the two tRNA
units now occupy the E and P sites.
* The spent tRNA dissociates from the E site and the process
is repeated.
when does the end of translation occur
The end of translation occurs
when the ribosome reaches one
or more STOP codons (UAA, UAG,
UGA).
describe inhibition with aminoglycosides
change the shape of 30s subunit
mis reading mRNA
bacteria lack proof reading mechanisms to deal with incorrect protein production
streptomycin
gentamycin
describe inhibition with tetracyclines
prevent amino acids from entering the ribosome at the 30s subunit
stalls protein synthesis
tetracyclines
minicyclin
doxycycline
eaxmples of tetracyclines
tetracyclines
minicyclin
doxycycline
exampes of aminoglycosides
streptomycin
gentamycin
how does streptomycin inibit protein synthesis
Streptomycin binds adjacent to the 30S decoding
site, forming hydrogen bonds and salt bridges with
backbone phosphates.
* Streptomycin distorts the ribosomal decoding site.
* Streptomycin preferentially stabilizes near-cognate
codon-anticodon interactions and thus induces
ribosomal misreading of the genetic code and
incorrect proteins are synthesised.
describe tetracycline structures
4 x 6-membered rings in a
linear arrangement
Phenol on left hand side
Natural products
Significant antimicrobial resistance
Semi-synthetic
Reserved for 2nd line treatment
when other drugs meet resistance.
describe 3rd generation, semisynthetic tetracyclines
Tigecycline
* Active against MRSA, VRE, many Gram negative
bacteria
* Efflux mechanisms of resistance can be a problem.
Properties and uses of tetracyclines
Orally absorbed
* Used to treat chest infections, acne, periodontal disease (and other non-
infection based conditions)
* Broad spectrum of activity: G+, G- bacteria, anthrax, Yersinia, Rickettsia
(typhus and Q fever), Chlamydia (trachoma, nonspecific urethritis),
mycoplasma, spirochaetes, Neisseria meningitidis.
* Doxycycline used in treating malaria
* Deposit in calcifying tissue (bone and teeth) causing staining, should not be
used in children under 8 yr or in pregnancy. Bone structure weakened.
* Good at binding metal ions – Ca2+, Zn2+, Fe3+, Al3+ [Why is this important?]
* OTHER EFFECTS! – anti-inflammatory
what is an example of inhibition of transpeptidation 1
Puromycin
Causes premature chain termination.
* Puromycin resembles the aminoacyl-tRNA
* It has an “NH” instead of the “O” that joins an amino acid
to tRNA
* The resulting stronger amide bond is not reactive enough
→ new peptide bond forms slowly.
* Ribosome stalls or incomplete protein chain is released.
what is an example of inhibition of transpeptidation 2
Chloramphenicol
Selective action on peptidyl transferase of the 50S subunit,
blocks the 50S ribosome, preventing peptide bond formation.
how any steroisomers are there of chloramphenicol
2 chiral centres
what is an example of inhibition of transpeptidation 3
Kanamycin
Kanamycin (an aminoglycoside) Causes misreading
of the code by interfering with the base pairing.
what is an example of inhibition of transpeptidation 4
Kirromycin
tRNA transfer is facilitated by 2 elongation factors
EF - Tu and EF - Ts
EF-Tu binds to GDP and GTP
GTP is hydrolysed and under goes a conformational change and dissociates
Kirromycin blocks this dissociation
Stalling protein synthesis
what is an example of inhibition of transpeptidation 5
Fusidic acid
Penetrates bone well, used in
staphylococcal osteomyelitis, also for
some MRSA infections
* Prevents translocation and EFG
dependent cleavage of GTP, also inhibits
80S EF2
* Does not enter mammalian cells.
* Inhibits the multiple-turnover EF-
G·GTPase. This stops ribosome
movement.
Inhibitors of Translocation 1
Macrolide Antibiotics
Macrolides bind to 50S ribosome and prevent movement from one codon to the
next, halting translation.
* Macrolides have a large ring system containing an ester linkage (in the ring)
* e.g. Erythromycin
eaxmples of inhibitors of termination
Inhibitors include Puromycin, streptogramins and some macrolides
ribosome structure
made up of two subunits
* The subunits lock around the messenger RNA and
then travel along the length of the messenger RNA
molecule reading each three-letter codon.
* The ribosome serves as a docking station for the
transfer RNA that matches the sequence of bases on
the messenger RNA.
* Each three-letter codon on the messenger RNA pairs
with the matching anticodon on a specific transfer
RNA, and that specific RNA allows for the addition of
a specific amino acid on the end of the growing
protein chain.
* When the ribosome encounters a stop codon, it falls
off the mRNA molecule and releases the protein for
use in the cell.
what is mRNA
Messenger RNA (mRNA) molecules carry the coding sequences for protein synthesis – “transcripts” -
dictates the order in which amino acids should be added to a growing protein as it is synthesised.
what is rRNA
Ribosomal RNA (rRNA) molecules form the core of a cell’s ribosomes
what is tRNA
Transfer RNA (tRNA) molecules carry activated amino acids to the ribosomes during protein synthesis
what is chloroquine
anti malarial agent
Chloroquine is used for the prophylaxis of malaria in areas
of the world where the risk of chloroquine-resistant
falciparum malaria is still low.
what is mefloquine
anti mlarial drug
Mefloquine is used for the prophylaxis of malaria in areas
of the world where there is a high risk of chloroquine-
resistant falciparum malaria
what is primaquine
antimalarial drug
Primaquine is used to eliminate the liver stages of P. vivax
or P. ovale following chloroquine treatment
what is proguanil
Proguanil is used (usually with chloroquine, but
occasionally alone) for the prophylaxis of malaria
what is pyrimethamine
Pyrimethamine should not be used alone, but is used with
sulfadoxine (in Fansidar)
describe the mechanism of chloroquine
Hemoglobin
(parasite metabolim)
Haem (Soluble & TOXIC!)
(bio-crystallisation)
Hemozoin (Insoluble non-toxic crystals)
chloroquite inhibits bio crystallisation
After passive diffusion, chloroquine becomes trapped in the
acidic parasitic digestive vacuole in the protonated form.
* Chloroquine caps hemozoin molecules to prevent further
biocrystallization of haem, → haem buildup.
* Chloroquine binds to haem to form a complex that is highly
toxic to the cell and disrupts membrane function.
* Toxic concentrations of haem and the complex → cell lysis
→ parasite cell autodigestion
what drugs intefere with the haem disposal mechanisms in
infected erythrocytes
Chloroquine, mefloquine, primaquine, quinine,
lumefantrine
what is proguanil
pro drug
produces cycloguanil
inhibits the parasites dihydrofolate reductase
it is thought that proguanil may act on another target also
what is the problem with proguanil
poor metabolism can decrease conversion of proguanil to cycloguanil in certain population african and asian
Pyrimethamine what does it do
It is a folic acid antagonist and inhibits the
dihydrofolate reductase of plasmodia → blocks
the biosynthesis of purines and pyrimidines.
* These are essential for DNA synthesis and cell
multiplication.
what does having a lot of chiral centres indicate
there will be an issue with synthesis
hard to synthesie
what is artemisinin
Artemisinin is a compound derived from the sweet wormwood plant (Artemisia annua). It is a potent antimalarial drug used to treat malaria, particularly strains that have developed resistance to other antimalarial medications. Artemisinin and its derivatives are often used in combination therapies to enhance their effectiveness and reduce the likelihood of resistance development. Artemisinin-based combination therapies (ACTs) are recommended by the World Health Organization (WHO) as a first-line treatment for uncomplicated malaria.
what are the other two analogues of artimisinin
artemether
artesunate
what is Artesunate
An injectable water-
soluble semi-synthetic
analogue
what is Artemether
A prodrug for
dihydroartemisinin
Artemether and
lumefantrine
combination therapy
Mechanism: interaction with heme, or ferrous ions, in the
parasite food vacuole → cytotoxic radical species.
* Artemether has a rapid onset of action and is rapidly cleared
from the body.
Lumefantrine has a much longer half life and is believed to
clear residual parasites
what is atovaquone
Highly lipophilic
* Acts by selectively affecting mitochondrial
electron transport and parallel processes
such as ATP and pyrimidine biosynthesis.
* Does not cause myelosuppression (important
for patients who have undergone bone
marrow transplantation)
what is Falciparum malaria
Falciparum malaria (malignant malaria) is caused by P.
falciparum. In most parts of the world P. falciparum is now
resistant to chloroquine which should not therefore be given
for treatment.
Drug treatment is by combination therapy, NOT monotherapy
what are Benign malarias
reccuring malarias
Chloroquine is the drug of choice for the treatment of
benign malarias (but resistance becoming widespread).
P. vivax and P. ovale
a radical cure (to
destroy parasites in the liver and thus prevent relapses)
is required.
This is achieved with primaquine
