the medicine Flashcards
1
Q
prokaryotic ribosome size
A
30s
2
Q
eukaryotic ribosome size
A
50s
3
Q
what are ribosomes responsible for
A
protein synthesis
Without functional ribosomes, bacteria
cannot survive. This is why ribosomes are
such an important target for new
antibiotics
4
Q
what are the 4 phases of bacterial protein synthesis
A
- Initiation
- Elongation (transpeptidation)
- Termination
- Ribosome recycling
5
Q
describe initiation
A
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.
6
Q
what do Oxazolidinones do?
A
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.
7
Q
what is transpeptidation, elongation
A
The amino acid at the P site is transferred to the amino acid
at the A site of the growing polypeptide chain
TRANSPEPTIDATION
8
Q
describe movement of ribosome from site letters
A
EPA
9
Q
describe elongation
A
- 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.
10
Q
when does the end of translation occur
A
The end of translation occurs
when the ribosome reaches one
or more STOP codons (UAA, UAG,
UGA).
11
Q
describe inhibition with aminoglycosides
A
change the shape of 30s subunit
mis reading mRNA
bacteria lack proof reading mechanisms to deal with incorrect protein production
streptomycin
gentamycin
12
Q
describe inhibition with tetracyclines
A
prevent amino acids from entering the ribosome at the 30s subunit
stalls protein synthesis
tetracyclines
minicyclin
doxycycline
13
Q
eaxmples of tetracyclines
A
tetracyclines
minicyclin
doxycycline
14
Q
exampes of aminoglycosides
A
streptomycin
gentamycin
15
Q
how does streptomycin inibit protein synthesis
A
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.
16
Q
describe tetracycline structures
A
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.
17
Q
describe 3rd generation, semisynthetic tetracyclines
A
Tigecycline
* Active against MRSA, VRE, many Gram negative
bacteria
* Efflux mechanisms of resistance can be a problem.
18
Q
Properties and uses of tetracyclines
A
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
19
Q
what is an example of inhibition of transpeptidation 1
A
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.
20
Q
what is an example of inhibition of transpeptidation 2
A
Chloramphenicol
Selective action on peptidyl transferase of the 50S subunit,
blocks the 50S ribosome, preventing peptide bond formation.
21
Q
how any steroisomers are there of chloramphenicol
A
2 chiral centres
22
Q
what is an example of inhibition of transpeptidation 3
A
Kanamycin
Kanamycin (an aminoglycoside) Causes misreading
of the code by interfering with the base pairing.
23
Q
what is an example of inhibition of transpeptidation 4
A
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
24
Q
what is an example of inhibition of transpeptidation 5
A
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.
25
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
26
eaxmples of inhibitors of termination
Inhibitors include Puromycin, streptogramins and some macrolides
27
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.
28
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.
29
what is rRNA
Ribosomal RNA (rRNA) molecules form the core of a cell's ribosomes
30
what is tRNA
Transfer RNA (tRNA) molecules carry activated amino acids to the ribosomes during protein synthesis
31
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.
32
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
33
what is primaquine
antimalarial drug
Primaquine is used to eliminate the liver stages of P. vivax
or P. ovale following chloroquine treatment
34
what is proguanil
Proguanil is used (usually with chloroquine, but
occasionally alone) for the prophylaxis of malaria
35
what is pyrimethamine
Pyrimethamine should not be used alone, but is used with
sulfadoxine (in Fansidar)
36
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
37
what drugs intefere with the haem disposal mechanisms in
infected erythrocytes
Chloroquine, mefloquine, primaquine, quinine,
lumefantrine
38
what is proguanil
pro drug
produces cycloguanil
inhibits the parasites dihydrofolate reductase
it is thought that proguanil may act on another target also
39
what is the problem with proguanil
poor metabolism can decrease conversion of proguanil to cycloguanil in certain population african and asian
40
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.
41
what does having a lot of chiral centres indicate
there will be an issue with synthesis
hard to synthesie
42
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.
43
what are the other two analogues of artimisinin
artemether
artesunate
44
what is Artesunate
An injectable water-
soluble semi-synthetic
analogue
45
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
46
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)
47
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
48
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
48
Prophylaxis against malaria
Protection against bites
Mosquito nets impregnated with permethrin
provide the most effective barrier protection against
insects; coils, mats and vaporised insecticides are also
useful
Diethyltoluamide (DEET)
n lotions, sprays or roll-on
formulations is safe and effective when applied to the
skin but the protective effect only lasts for a few hours.
Long sleeves and trousers worn after dusk also provide
protection.
49
Global warming and its effect on mosquito range
As the world warms, the mosquito range moves northwards.
This could potentially expose many new populations to
mosquito-born diseases.
50
what is Trypanosomiasis
Human African trypanosomiasis (sleeping sickness) is a
widespread tropical disease that can be fatal if not treated.
Spread by the bite of an infected tsetse fly.
affecting CNS
51
Trypanosomiasis treatment
Pentamidine, Berenil, Eflornithine for prophylaxis and
treatment
Tryparsamide and Melarsoprol toxic arsenic compounds
needed in advanced cases
52
what is Suramin
For first stage treatment
of Trypanosoma brucei
rhodesiense sleeping
sickness
53
why is sumarin used parenterally
it has very poor oral bio abvailibility
54
Trypanosomiasis – symptoms
The bite erupts into a red sore and within a few weeks
the person can experience fever, swollen lymph glands,
aching muscles and joints, headaches and irritability.
* In advanced stages, the disease attacks the central
nervous system (crosses the BBB), causing changes in
personality, alteration of the biological clock, confusion,
slurred speech, seizures, and difficulty walking and
talking. If not treated, the person will die.
55
Stage 1: in subcutaneous tissues, blood and lymph, treatment
The drugs used in the first stage of the disease are of lower
toxicity and easier to administer. The earlier the disease is
identified, the better the prospect of a cure.
56
Stage 2: the parasites cross the blood-brain barrier to infect
the central nervous system, treatment
Second stage drugs have to cross the blood-brain barrier to
reach the parasite. Such drugs are toxic and complicated to
administer.
57
what is Pentamidine
For first stage treatment of Trypanosoma brucei gambiense
sleeping sickness
* Despite its undesirable effects (which include liver or
kidney dysfunction, hypertension, hypotension,
hypoglycemia, hypocalemia, leukopenia, thrombcytopenia,
anemia, and allergic reaction), it is in general well tolerated
by patients. (!)
* It is thought that the drug interferes with nuclear
metabolism producing inhibition of the synthesis of DNA,
RNA, phospholipids, and proteins.
58
what is Melarsoprol
Second stage treatment
for both forms of infection
Crosses the blood-brain barrier
* It is derived from arsenic and has many undesirable side
effects: cutaneous reactions, polyneuropathy, diarrhoea and
fever and reactive encephalopathy (encephalopathic
syndrome) which can be fatal (3% to 10%).
* An increase in resistance to the drug has been observed in
several foci particularly in central Africa.
59
what is Eflornithine
Second stage treatment but
only for T. gambiense
Less toxic than melarsoprol
* Crosses the blood-brain barrier
* The regimen is strict and difficult to apply.
* A combination treatment of nifurtimox and eflornithine
introduced in 2009.
60
what is the mechanism of action of Eflornithine
Enzyme-activated, irreversible inhibitor of ornithine
decarboxylase (ODC), the key enzyme in the conversion of
ornithine to polyamines.
Polyamines are essential for nucleic acid and protein
synthesis in protozoa.
61
what catalyses the change in the mechanism of action
Di floro mthyl group,
62
what is Leishmaniasis
sand fly vector
Leishmania tropica and Leishmania donovani cause cutaneous
(Baghdad boil, Dehli sore, oriental sore, Kala-azar, chiclero
disease) and visceral infection (liver and spleen).
63
Leishmaniasis agents
Pentamidine, amphotericin, antimony compounds
(sodium stibogluconate)
64
what is Amphotericin B
A polyene antibiotic
* second line of treatment for visceral leishmaniasis
use restricted by its acute toxicity, low therapeutic index
and the need for parenteral administration.
65
what is Sodium Stibogluconate
The mechanism of action is possibly something to do
with a reduction in ATP and GTP synthesis leading to
decreased macromolecular synthesis.
Leishmaniasis treatment
66
what is Chagas’ disease
Trypanosoma cruzi transmitted by bites to face by
reduviid bug (Mexico, South America).
* Invades heart muscle (sudden heart failure)
* damages nerves in GI tract (mega colon).
67
treatment agents for Chagas’ disease
Nifurtimox and Benznidazole
68
similaries between Nifurtimox and Benznidazole
The nitro group of both drugs is reduced to an amino group
by the action of nitroreductases, with the formation of
various free radical intermediates and electrophilic
metabolites
69
mechanism of Nifurtimox
intracellular reduction → nitro radical followed
by redox cycling, and production of O2− and H2O2 is the
main mechanism of action of against T. cruzi.
70
mechanism of Benznidazole
It is likely that the reduced metabolites of
benznidazole are involved in its trypanocidal effects by
covalent bonding to macromolecules.
71
what is Amoebiasis
Entamoeba histolytica
* lives in the gut (harmless cyst form)
* can invade gut mucosa (amoebic dysentery)
* secondary spread (liver abscesses)
72
agents for amoebiases
Metronidazole, tinidazole and diloxanide
73
what is Metronidazole
Enters the cell as a prodrug by passive diffusion and is
activated by reduction of the nitro group in specific
organelles in the protozoa.
* The activated forms are cytotoxic and can interact with the
DNA molecule → inhibition of DNA synthesis and DNA
damage by oxidation → single-strand and double-strand
breaks → DNA degradation and cell death.
74
what are the two possible genotoxic pathways for nitro group reduction
anerobic and aerobic
75
describe the anerobic pathway for nitro group reduction
formation of the nitro redical anion
further reduction occurs via the formation of nitroso and hydroxylamin derivatives
ultimate products are the primary amines
hydroxyl radicals could induce single and double strand breaks
hydroxyl amino acid groups could form DNA adducts
76
describe the aerobic pathway for nitro group reduction
formation of the nitro redical anion
radical is rapidly oxidised by O2
produces superoxide and hydroxide radical anions.
77
what is Tinidazole
A synthetic antiprotozoal agent
similar to metronidazole
It is
suggested that the toxic free radicals covalently bind to
DNA → DNA damage → to cell death.
78
what is Diloxanide [furoate]
An anti-protozoal drug used in the treatment of
Entamoeba histolytica and some other protozoal
infections.
* Mechanism unknown - may inhibit protein
synthesis
* Destroys the trophozoites of E. histolytica that
eventually form into cysts. The cysts are then
excreted by persons infected with asymptomatic
amebiasis.
* Diloxanide furoate is a prodrug and is hydrolysed
in the gastrointestinal tract to produce diloxanide,
the active ingredient.
79
what is Giardiasis
Giardia lamblia lives in gut, does not invade tissues,
* Causes chronic diarrhoea
80
agents for giardiasis
Metronidazole, tinidazole, mepacrine
81
what is Mepacrine (Quinacrine)
Exact antiparasitic mechanism
unknown
* Binds to DNA in vitro by intercalation
between adjacent base pairs,
inhibiting transcription and translation
to ribonucleic acid (RNA).
Mepacrine (Quinacrine)
* Does not appear to localize to the nucleus of Giaridia
trophozoites, suggesting that DNA binding may not be
the primary mechanism.
82
what is Trichomoniasis
Trichomonas vaginalis present in the urogenital
system, sexually transmitted, vaginitis
83
agents Trichomoniasis
Agents: Metronidazole, tinidazole
84
what is Pneumocystis carinii pneumonia (PCP)
Pneumocystis carinii present in lungs as cyst form.
* HIV infection leads to activation of organism and fatal
pneumonia.
85
agents for Pneumocystis carinii pneumonia (PCP)
Pentamidine, trimethoprim, sulphonamides,
atovaquone and trimetrexate
86
what is Trimethoprim
Trimethoprim is a pyrimidine analogue that inhibits DHFR
and disrupts folate synthesis (an essential part of the
thymidine synthesis pathway) → starves the organism of
nucleotides necessary for DNA replication.
87
what is Trimetrexate
Trimetrexate is a competitive inhibitor of protozoan DHFR.
88
what is Toxoplasmosis
Toxoplasma gondii transmitted from cat faeces, lamb,
beef. Causes glandular fever-like condition, severe
consequences in first trimester of pregnancy (effects on
foetus).
89
agents for Toxoplasmosis
Agents: Pyrimethamine, sulphonamides, clindamycin,
* clarithromycin, azithromycin (used in new-born
prophylaxis of eye infections)
90
what is Clarithromycin
Clarithromycin is first
metabolized to 14-OH
clarithromycin, which is active
and works synergistically with its
parent compound
Like other macrolides, it then penetrates bacteria cell wall
and reversibly binds to domain V of the 23S ribosomal
RNA of the 50S subunit of the bacterial ribosome,
blocking translocation of aminoacyl transfer-RNA and
polypeptide synthesis.
91
what is clindamycin
ClindamycinAzithromycin, a semisynthetic
antibiotic belonging to the
macrolide subgroup of azalides
92
what is Azithromycin
Azithromycin, a semisynthetic
antibiotic belonging to the
macrolide subgroup of azalides
93
what is Cryptosporidiosis
Cryptosporidium parvum present in water contaminated with
animal faeces.
* Invades and reproduces in epithelial cells of small intestine.
* Causes severe diarrhoea
common in HIV
94
agents for Cryptosporidiosis
No routine treatment available, macrolide spiramycin
used in HIV
95
what is Spiramycin
A 16-membered macrolide
* Inhibits translocation by
binding to bacterial 50S
ribosomal subunits.
* Potent inhibitor of the
binding to the ribosome of
both donor and acceptor
substrates. Spiramycin
induces rapid breakdown of
polyribosomes.
96
tell me about metrondiazole as an antibacterial agent
Metronidazole is an antibacterial and antiprotozoal medication used to treat a variety of infections caused by certain bacteria and parasites
97
tell me about metrondiazole MOA
enters cell as prodrug
via passive diffusion
activated by redution of nitro group
in specific organelles in proteoza
activated forms are cytotoxic
can interact with DNA
inhibits DNA synthesis and causes damage
via oxidation
single and double strand breaks
DNA degredation and cell death
98
tell me about nitrofuratonin similar MOA to metrondiazole
used for UTIs
99
tell me about rifampin
semisynthetic antibiotic
obtained by reacting 3-formylrifamycin and 1-amino-4-methylpiperazine
100
tell me about MOA of rifampin
inhibits bacterial RNA polymerase (responsible for RNA transcription) by forming a stable drug-enzyme complex
mammalian enzumes are not effected ny rifampin
bacterial resistance yo rifampin is caused by mutations leading to a change in the structure of the beta subunit of RNA polymerase
101
what does DNA helicase do
promotes strand seperation at the replication fork
102
what does DNA polymerase III do?
primary enzyme of replication, attaches nucelotides to the growing DNA chain and proof reads.
103
what does DNA polymerase I do?
fills in gaps on lagging strand and removes RNA primers
104
what is primase
makes short RNA primers for the lagging strand
105
what do topoisomersases I do?
relax supercoiled DNA
106
what do topoisomerases II do?
DNA gyrase, promotes negative supercoiling and maintains the shape of the chromosome
introducing double-strand breaks
107
what do topoisomerases III do?
removes negaive supercoiling
Resolves DNA knots and catenanes by introducing double-strand breaks and passing DNA duplexes through each othe
108
what topoisomeraes IV do?
removes knots and links behind replication fork
introducing transient double-strand breaks and passing one DNA duplex through another,
109
how do quinolones inhibit DNA
inhibit DNA gyrase
block re sealing of bacterial DNA strands on supercoiling
causign bacterial chomosomes to break into multiple fragments
quinolones are 100 X more active against bacterial vs human gyrases
110
what is antigene oglonucleotides
antigene stratigies require triple forming oglionucleotides TFOs
these form triple helical structures with duplex DNA targets
Antigene oligonucleotides in TFOs are synthetic DNA or RNA molecules designed to bind to specific DNA sequences within a gene's promoter region. By binding to these sequences, they interfere with the binding of transcription factors or RNA polymerase, ultimately inhibiting gene expression.
111
purine bases targeting
targeting achievable by 2 hoogsteen hydrogen bonds
111
what is Tm
the melting temp
the temp at which 50% of dissociation of triple helix into TFO and double helix or dissociation of double helix int single strandec coil
112
pyrimidine bases targetting
targeting achievable by 1 hoogsteen hydrigen bond
113
what is TFO design limited to
limited to polypurine targets unlike antisense ddesign
114
tell me about hoogsteen paired TFOs
pyrimidine TFOs form isomorphous triplex structures
there is a need for protonation of cytosine N3 imparts pH instablity
replacement of H by CH3 at C5 is stabilising but only marginally
115
tell me about pH independed G,A containing TFOs
they form stable triplexes over a wide pH range esp 7.2
GGA and AAT triplexes are not isomorphous , they still need improving
umodified DNA backbone is easily hydrolysed in vivi, therefore a short half life
116
targeting DNA gyrase in E.coli
stable at pH 7.2
Tm vale is 30 degrees celcius
bacterial growth is inhibited by the prescence of TFOs vs abscence control
TFO is bacteroistatic wheras fluroquinolones are bacteriocidal
117
tell me about TFO backbones
LNA monomers are comercially available
LNA resists enzymatic hydrolysis so there is a longer half life, in vivo
LNA is more A-DNA and RNA like in conformation
all LNA backbone oglios suffer from self pairing
typical solution to self pairing is to form chimeric oligos
118
what is an LNA
locked nuclaic acid
119
