L6 - Antibacterials : protein synthesis Flashcards
What is a pre-ribosomal stage inhibitor?
mupirocin: isoleucyl tRNA synthetase inhibitor
What are ribosomal inhibitors?
oxazolidinones tetracyclines aminoglycosides chloramphenicol macrolides
What is an indirect ribosomal inhibitor?
fusidic acid
What are the 3 stages of protein synthesis?
initiation
elongation
termination
What are the 3 sites within the ribosome?
A-site
P-site
E-site
What are generalised feature of antibacterial drugs targeting protein synthesis?
act on ribosome
bacteriostatic
What are things that allow for selective toxicity?
difference between 70S and 80S ribosomes
How is Mupirocin selectively toxic?
structural diff between prok and euk isoleucyl-tRNA synthetases
How is fusidic acid and tetracycline selectively toxic?
different uptake in eukaryotic and prokaryotic cells
What is the main side effect of ribosomal inhibitors?
inhibition of mitochondrial protein synthesis - similar to bacterial
endosymbiotic theory!
How does mupirocin work?
substrate analogue to inhibit isoleucyl tRNA synthetase
What is the role of isoleucyl tRNA sythetase?
amino acids are linked to a tRNA adaptor
specific aminoacyl-tRNA synthetase responsible for joining the 2 components
What is the clinical use of mupirocin?
NARROW - cannot infect gram neg due do the outer membrane
treats staph and strep skin infections
eliminate nasal MRSA
Why is mupirocin not applied systemically?
it would be rapidly de-esterified in kidney & liver
What are the 2 oxazolidinones?
Linezolid
Tedizolid
Facts about oxazolidinones?
bacteriostatic
Gram +ve only
bind on 50S ribosomal subunit
How do oxazolidinones work?
LZD interferes with binding/correct positioning of the initiator tRNA in the p-site during the initiation process
What are the clinical uses of oxazolidinones?
pneumonia
skin/soft tissue infections
What are the side effects of LZD?
skin
gastrointestinal disturbance
liver function abnormalities
thrombocytopenia
anaemia
How is TZD better than LZD?
reduced myelosuppression
increased antibacterial potency = SHORTER COURSE OF TREATMENT = LESS SIDE EFFECTS
What are tetracyclines?
broad-spectrum action
bind to A-site within 30S subunit
How do tetracyclines work?
prevent association of aminoacyl-tRNA with the ribosome
What is the 3rd generation tetracycline?
Tigecycline
How is tigecycline applied?
IV ONLY for skin. soft tissues & abdominal infections
What are adverse effects of tetracyclines?
gastrointestinal disturbances
photosensitivity
CNS effects
deposition in bones/teeth
What is one of the only bactericidal drugs?
Aminoglycosides
How do aminoglycosides work?
bind to 30S subunit via 16S rRNA
OR
bind BOTH 30S and 50S subunits
What do aminoglycosides inhibit?
ribosomal translocation - peptidyl-tRNA moves from A to P site
cause MIS-READING OF mRNA = abnormal proteins
What does aminoglycoside look for?
watson-crick base pairing between codon and anti-codon
reduces translation fidelity
How does aminoglycoside actually kill cells?
Non-functional proteins
increased number of external hydrophobic patches
escape environment by burying in membrane - disruption and leakage
What are aminoglycosides used for?
sepsis
plague
enterococcal endocarditis
combination therapy for TB and Gram-pos infections
What are adverse side effects of aminoglycosides?
ototoxicity
nephrotoxicity
neuromuscular blockade
What is chloramphenicol?
true broad-spectrum
treats typhoid & paratyphoid fever
How does chloramphenicol work?
binds to 50S subunit at PTC - covers the a-site
blocks aa-tRNA binding
What are adverse side effects of chloramphenicol?
myelosuppression
Gray syndrome
What are Macrolides?
macrocyclic lactone ring with AMINO SUGAR and another sugar attached
What is one of the worlds’ best-selling antibacterial agents?
azithromycin
How is azithromycin better than eryhtromycin?
greater coverage for gram neg respiratory tract pathogens
What is the mode of action of macrolides?
bind to 23S rRNA at peptide exit site - 50S subunit
block exit
premature dissociation of peptidyl-tRNA from P-site
How can macrolides be administered?
Oral
IV
What are adverse side effects of macrolides?
gastrointestinal disturbances
jaundice
ototoxicity
Why is oral administration not always good for macrolides?
erythromycin - acid labile
gastric degradation
What is the mode of action of fusidic acid?
interferes with release of elongation factor G from ribosome
locks onto ribosome
stops EFG from conformational change that would have led to dissociation
What are clinical uses of FA?
limited to gram pos
topical, oral, IV
What are adverse side effects of FA?
rashes
jaundice
How can protein synthesis inhibitors be used as adjunctive therapy?
REDUCE TOXIN PRODUCTION
TOXINS PRODUCED BY BACTERIA = SYMPTOMS
