Glossary of Block 4: Antibiotics- inhibition of nucleic acid synthesis

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selectivity of sulfonamides based on...
bacteria synthesize folic acid; mammalian cells lack enzymes required to synthesize folate
MOA of sulfonamides
broad spectrum bacteriostatic

structural analogs and competitive antagonists of PABA at dihydropteroate synthase
name four classes of sulfonamides
oral absorbable
long acting
sulfonamide distribution?
cross BBB?
cross placenta?
broad distribution
crosses BBB and placenta
name three mechanisms of resistance to sulfonamides
1. decreased bacterial permeability/influx
2. active efflux
3. increased PABA, decreased sensitivity of synthase
go from PABA to DNA
PABA -> (dihydropteroate synthase) ->
dihydrofolic acid -> (dihydrofolate reductase) -> tetrahydrofolic acid -> purines ->
what inhibits dihydropteroate synthase
what inhibits dihydrofolate reductase
name four adverse effects of sulfonamides
1. crystalluria- better w/ triple sulfa combo due to decreased chance of precipitation of any one drug
2. hematopoietic
3. hypersensitivty
4. GI
name three drugs potentiated by sulfonamides
1. oral anticoagulants
2. sulfonylurea hypoglycemics
3. hydantoin antiseizure drugs
name two benzylpyrimidines
are benzylpyrimidines bacteriocidal or bacteriostatic
benzylpyrimidine MOA
selective inhibitor of bacterial isoform of DIHYDROFOLATE REDUCTASE
(there is a mammalian form of this enzyme but it is less sensitive)
benzylpyrimidine route of administration...
crosses BBB?
crosses placenta?
significance of being a weak base?
oral admin (or iv w/ sulfamethoxazole)
broad distribution
crosses BBB
crosses placenta
weak base -> trapped in prostate and vaginal fluids
name two mechanisms of resistance to benzylpyrimidines
1. decreased bacterial permeability/influx
2. inc production of reductase; dec sensitivity of reductase
name three adverse effects of benzylpyrimidines
megaloblastic anemia
what happens when you combine sulfamethoxazole with trimethoprim
synergism from sequential blockade of folate synthesis
what is an adverse effect of combining sulfamethoxazole with trimethoprim and what patient population is particularly susceptible
CNS disturbances
esp in AIDS patients
how do drugs that inhibit DNA duplication and transcription achieve selectivity
bacteria have DNA gyrase
mammalian cells don't
(we do have type II DNA topoisomerase that can be inhibited by quinolones, but only at very high levels)
fluoroquinolones bactericidal or bacteriostaic?
gram neg or gram pos targets?
mostly gram neg
some gram pos
fluoroquinolone MOA for gram negatives
inhibits DNA gyrase (topoisomerase) ->
prevents relaxation of positively supercoiled DNA required for transcription and replication
fluoroquinolone MOA for gram positives
inhibit topoisomerase IV -> interferes w/ separation of replicated DNA into daughter cells during division
fluoroquinolone route of admin?
oral admin
broad distribution
renal clearance
two mechanisms of resistance to fluoroquinolones
1. decreased bacterial permeability/influx
2. decreased affinity of DNA gyrase and/or topoisomerase IV
what do fluoroquinolones cause when given to pregnant women, nursing mothers or children
cartilage damage
name a drug interaction of fluoroquinolones
increases theophylline (*treatment for asthma)
name a nitroimidazole
what bugs are susceptible to nitroimidazoles
anaerobes, esp vancomycin-resistant c. difficile
nitroimidazole MOA
inhibits DNA rep -> the nitrosohydroxyl amino moiety is reduced by an electron transport protein in anaerobic bacteria -> causes strand breaks in DNA
*mammalian cells don't have the enzymes to reduce the nitro group -> therefore unharmed
nitroimidazole rout of admin
metabolized by __ and __
liver CYP3A4 hydroxylation
renal clearance
mechanism of resistance to nitroimidazoles
unknown, but it exists
name three adverse effects of nitroimidazoles
1. leukopenia
2. reduce doses in pt's w/ reduced liver function
3. seizures and peripheral neuropathy after prolonged therapy
name two drug interactions of nitroimidazoles
1. barbituates decrease nitroimidazole half life
2. nitroimidazole inhibits alcohol metabolism
name four bugs susceptible to rifamycin (rifaximin)
Traveler's diarrhea E. coli
other enteropathogens
rifamycin MOA
inhibits bacterial RNA synthesis- non-covalently binds to beta subunit of DNA-dependent RNA polymerase
rifamycin oral absorption
poor! ~.4% -> mostly excreted unchanged in feces
mechanism of resistance to rifamycin
small amino acid mutations in RNA polymerase beta subunit
which liver enzyme is induced by rifamycin
genetically encoded resistance to glycosaminoacids
change of D-Ala-D-Ala substrate
genetically encoded resistance to beta lactams
beta lactamase activity
genetically encoded resistance to tetracylcine
Tet-O resistance (proteins block the antibiotic)
genetically encoded resistance to oxazoladinones
mutation of target (23S rRNA of the 50S ribosomal subunit)
action of the combination is significantly greater than the sum of the actions of each component
imipenem (beta lactam) + cilastatin (renal dipeptidase inhibitor)=
primaxin - inhibition of inactivating enzymes
amoxicillin (beta lactam) + clavulonate (beta lactamase inhibitor) =
augmentin - inhibition of inactivating enzymes
ticarcillin (beta lactam) + clavulonate (beta lactamase inhibitor) =
timentin - inhibition of inactivating enzymes
amoxicillin (beta lactam) + sulbacatam (beta lactamase inhibitor) =
unasyn - inhibition of inactivating enzymes
pipercillin (beta lactam) + tazobactam (beta lactamase inhibitor) =
zosyn - inhibition of inactivating enzymes
trimethoprim (benzylpyrimidine) + sulfamethoxazole (sulfonamide) =
bactrim - sequential inhibition of successive steps in metabolism (and bacteriostatic to bactericidal)
erythromycin (macrolide) + sulfisoxazole (sulfonamide) +
inhibition of development of resistance by blocking two unrelated pathways
beta lactam + aminoglycoside
inhibition of development of resistance by blocking two unrelated pathways
what is the effect if two antimicrobials compete for the same binding site
each site can only be inhibited once -> you just wasted some money

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