Part 3: Antimicrobial Inhibitors of Bacterial Protein Synthesis Flashcards
bacteria have ____ ribosomal subunits and humans have ____ ribosomal subunits
30S & 50s; 40S & 60S
what are the 3 main classes of protein synthesis inhibitors?
tetracyclines, aminoglycosides, macrolides
t/f protein synthesis inhibitors can be bacteriostatic or bactericidal
true
besides the 3 main classes, what are 2 other drugs that act by protein synthesis inhibition?
clindamycin and chloramphenicol
doxycycline is from the ____ family of antibiotics
tetracycline
tetracyclines are ___ spectrum
broad
describe the structure of tetracyclines
4 fused rings
what part of a tetracycline structure cannot be altered, or activity will be lost?
the O2 groups at the top
what part of a tetracycline can be changed without loss of activity
R groups along the bottom
altering the R groups of a tetracyline alters the ____ properties
pharmacokinetic
tetracyclines bind to the ___ subunit near the ___ site
30s ; A
the binding of a tetracyline to a bacterial ribosome prevents ___ from binding, which prevents the elongation of the ___
tRNA; bacterial peptide chain
what are 3 mutations that make bacteria more resistant to tetracyclines?
mutation in the 30s that reduce drug binding ; efflux pumps; enzymes that break down drug structure
t/f tetracylines are typically inly used to target a specific infection due to the prevalenace of mutations and resistance
t
the O2 containing groups along the top of the tetracyline structure bind strongly to ____
cations (mg, ca, Fe, Zn)
when tetracylines bind to a cation it is called ___
chelation
why is the binding of tetracylines to cations problematic?
can bind to calcium in developing teeth and discolour them; if taken with dairy they cant be absorbed very well (too big) so they are less effective
why are tetracylines less of an issue for people with developed teeth?
bc as adults the bone matrix os constantly changing, so tetracyline will eventually be replaced
tetracylines can cause an increase sensitivity to ___
sunlight
why do tetracylines cause skin rashes and sunburns when patients are exposed to sun?
tetracyline accumulates in the skin
gentamicin is an example of a ___ antibiotic
aminoglycoside
aminoglycosides bind to the ____subunit
30s
how do the aminoglycosides bind to the 30s subunit?
covalently (irreversibly)
what is the reason for the long post-antibiotic effect of aminoglycosides?
their covalent binding to the 30s subunit
aminoglycosides cause a disruption in the ___ of the ribosome subunit
shape
when aminoglycosides cause a shape change in the 30s, what i sthe result?
mRNA reading frame becomes distorted, leading to the wrong AA being added to the peptide chain
aminoglycosides also impair the translocation of the peptide, meaning ___
the growing chain is not able to move as easily from the A site to the P site b/c of obstruction caused by drug
aminoglycosides cause newly formed bacterial proteins to be ___
dysfunctional; or not even made
aminoglycosides binding to the 30s can also impair proper formation of the ribosome complex, which prevents ____
initiation of protein synthesis
aminoglycosides are _____ (cidal or static_
cidal
aminoglycosides are ____ spectrum
broad
aminoglycosides have particularly good activity against Gram ____
negative
why do aminoglycosides have good activity against G-?
their structure (several linked sugars and amino groups) are substrates for the G- pores
t/f increasing the concentrations of aminoglycosides inside bacterial cells increases the bactericidal effecst
true
adding what type of antibiotic with an aminoglycoside would result in significant synergistic effect?
cell wall inhibitor like a beta lactam
why would a beta lactam and an aminoglycoside have a synergistic effect?
beta lactam breaks down the wall, letting more aminoglycoside in
aminoglycosides are not suitable for ____(route) dosing
oral
why are aminoglycosides given by IV?
they have poor oral bioavailability
aminoglycosides have ____ dependent bactericidal effects
concentratio
what are some ADRs of high dose aminoglycosides
irreversible hearing loss, damage to the kidneys
why are blood levels carefully monitored for patients on IV aminoglycoside?
dont want too high dose that would cause aADRs
bacterial resistance to aminoglycosides typically occurs by ____
bacteria reducing entry or inactivating it in the cytoplasm
aminoglycosides can be inactivated by beta lactams if ___
they are direltly mixed togther
t/f the binding of a beta lactam ring to an aminoglycoside results in the inactivation of both drug
t
what is the key difference between tetracylines and aminoglycosides?
aminoglycosides bind irreversibly
macrolides bind to the ____ subunit
50s
what is the MOA of macrolides?
binding to the 50s prevents translocation of growing peptide from A site to P site and it also blocks the peptidlu transferase rxn which links new AA to the growing chain
give 3 examples of macrolide antibiotics
erythromycin, azithromycin, clairithromycin
what was the 1st macrolide used clinically?
erythromycin
which macrolides are more typically used today? why?
clairithromycin and azithromycin bc they have fewer drug interactions
what is the characteristic structure of macrolides?
the large open ring (macrolide ring)
t/f macrolides have several R groups that can be varied to give the diffrent drugs in the family
t
what is the role of the large macrolide ring?
significant interference with the ribosomal complex structure, leading to many dysfunctions
binding of macrolides is _____
reversible
what happens is macrolide concentrations are too low?
some protein synthesis can still occur (growth only slowed)
at high concentrations of macrolides, the effect can be ___
bactericidal
macrolides have ____ spectrum
broad
macrolides are commonly used if a pateint has an allergy to ___
beta lactams
how does resistance to macrolides typically occur? (3)
mutations of the 50s at the binding site; increased efflux; ezymatic breakdown of the ring
resistance to macrolides is less common than resistance to ___
tetracylines
resistance to macrolides is most common in ____ infections
oral
erythromycin and clairithromycin are known to inhibit host ___ enzymes
CYP450; particularly CYP 3A4
why is it an issue that erythromycin and clairithromycin inhibit CYP 3A4 enzymes?
many drugs are metabolized by this enzyme, so it can lead to toxic build up of other drugs (or too low levels of prodrugs)
what is unique about azithromycin?
does not impact CYP and has a very long half life, so it can be given as one large daily dose
what is the half life of azithromycin?
12 hours
is azithromycin renally excreted>
no
clindamycin binds to the ___ subunit
50 s
clindamycin has some of the same properties as ___ antibiotics
macrolide
why is clindamycin not a member of the macrolide family?
does not have the macrolide ring
MOA of clindamycin
binds to 50s and prevents bacterial peptide translocation from A to P
at doses used clinically, clindamycin is ____ (cidal or static?
static
the spectrum of activity of clindamycin makes it particularly useful for treating ____ infections
oral
clindamyin is effective against G____ and. some G____
+ and some -
t/f clindamycin is effective against some anaerobes
true
clindamyin may be a drug of choice for those with a ____ allergy
penicillin
resistance patterns to clindamycin? (3)
change binding site, efflux, enzymatic inactivation
t/f chloremphenicol is not used much in North America, but still used in other places
t
chloremphenicol binds to the ___ subunit
50s
the MOA of chloremphenicol is similar to that of ___
macrolides
MOA of chloremphenicol
bind 50s and prevent bacterial peptide elongation and peptidyl transferase rxn
chloremphenicol is a ___ spectrum
broad
bacterial resistance to chlorempheicol
not as commonly, but by enzymes that break down the drug
chloramphenicol distributes ___ to the tissues in the body, especially the CNS
extensively
what is a unique ADR to chloramphenicol?
aplastic anemia
what is the big deal if chloramphenicol casues aplastic anemia?
low levels of WBC can reduce host immune response (counter-productive to the treatment)
t/f chloramphenicol has a high rate of metabolism into ___
inactive metabolites
chloramphenicol inhibits _____, which results in many ___
CYP450; drug interactions
when might chloramphenicol be used?
for very specific cases (meningitis) or if nothing else is available
