Exam 5—Antibiotics Flashcards
starting material for cell wall is ——-, which is turned into ——-
UDP-N-acetylglucosamine
N-acetyl muramic acid
——- side chain is added to cell wall after muramic acid
pentapeptide
in GPs, a ——- is added to L-lysine on cell wall
pentaglycine
binds and transports wall “units” across cytoplasmic membrane
bactoprenol (undeceprenyl)
transglycosylation creates…
creates the β1-4 bonds
transpeptidation creates…
creates peptide cross links between diaminopimelic acid and D-Ala (GNs) or D-Ala and Gly (GPs)
transpeptidation is performed by…
transpeptidase AKA penicilin-binding protein (PBP)
B-lactam target
PBP
—– makes an alternative PBP, to which B-lactams do not bind
MRSA
B-lactams inhibit the PBP, but what actually destroys the cell?
autolysins, destroying cell wall that the cell cannot replace
stimulate autolysin activity
free peptides
B-lactam drugs
penicillins
cephalosporins
carbapenems
monobactams
essential structure of B-lactam
warhead
glycopeptide/lipopeptide mechanism
Cell wall synth
Bind to D-Ala-D-Ala and inhibit both transglycosylation and transpeptidation
glycopeptide/lipopeptide drug
vancomycin
Vancomycin treats Gram —-
positives
especially MRSA
Fosfomycin & bacitracin mechanism
cell wall synth
Fosfomycin irreversibly inactivates enzyme that converts UDP-glucosamine to UDP-muramic acid
Bacitracin blocks recycling of bactroprenol
cell wall antibiotic only used topically
bacitracin
structure of fosfomycin
epoxide bridge
fosfomycin used to treat…
MRSA
UTIs
target 50s of ribosome
macrolides
chloramphenicol
lincosamides
streptogramins
everninomycins
oxazolidinones
target 30s of ribosome
aminoglycosides
tetracyclines
important in recognizing AUG start codon
30s
aminoglycoside mechanism
bind 16s rRNA of small subunit
large subunit is prevented from joining
aminoglycoside drugs
kanamycin
gentamicin
serious side effects of aminoglycosides
hearing loss
kidney impairment
tetracycline mechanism
Binds 16s rRNA of small subunit
large subunit joins, but A site is distorted, and tRNA cannot align with codon on mRNA
tetracycline used to treat…
Lyme
chlamydia
gonorrhea
acne
in animal feed
side effect of tetracycline
graying of teeth if used for longer periods
macrolide drugs
erythromicin
azithromycin
macrolide mechanism
23s rRNA of large subunit, blocking the exit tunnel
erythromycin use
animal feed
azithromycin use
chlamydia
gonorrhea
advantage of azithromycin, used for sex workers
long lasting with only one or two doses needed
lincosamide mechanism
binds 23S rRNA of large subunit, blocking the exit tunnel
lincosamide drug
clindamycin
clindamycin use
obligate anaerobes
Bacteroides
Giardia parasite
C. difficile
nucleic acid synth inhibitors are ——- inhibitors
DNA gyrase (topoisomerase I and II)
DNA gyrase drugs
quinalone
norfloxacin
ciprofloxacin
fluoroquinalone
part of quinalone that inhibits DNA gyrase
nalidixic acid
gyrase inhibitor mechanism
this induces cleavage of DNA and inhibits closing of nicks formed in supercoiling mechanism
DNA cannot be packaged into new cell
best tx for anthrax
fluoroquinalone/cipro
fluoroquinalone/cipro makes a good choice because of poor action against…
microbiota
metronidazole mechanism
active form degrades DNA
inactive form of metronidazole is taken, and it is converted to active form by…
ferredoxins and flavodoxins found in obligate anaerobes (not in human cells)
metronidazole used against…
amitochondriate parasites Giardia and Trichomonas
RNA synthesis drug
rifampin
rifampin mechanism
binds β-subunit of core polypeptide of RNA polymerase in bacteria
blocks mRNA exit tunnel
rifampin used against….
M. tuberculosis
folic acid synth drugs
sulfonamides
trimethoprim
folic acid required for…
1-C metabolism in nucleic acid and protein synthesis
Prototrophic bacteria synthesize folic acid from —-
PABA
sulfonamide mechanism
analogs of PABA and inhibit dihydropteroid acid synthesis
trimethoprim mechanism
analog of dihydrofolate and inhibits dihydrofolate reductase
SXT =
sulfonamide + trimethoprim
SXT used to ID…
Used to identify S. pneumoniae (susceptible) and S. pyogenes/S. agalactiae (resistant)
4 main methods of resistance
- modification of target
- limiting access
- enzymatic inactivation
- failure to activate drug
limiting access strategies
outer membrane porin reduction
reduced uptake
active efflux
allow drug entry to periplasm of GNs
porins
how can mutation change porins for resistance?
Mutation can eliminate porins, reduce diameter, prevent uptake, or decrease expression
mutations not involved in preventing uptake of ——-
aminoglycosides
——– are not affected by limiting access method of resistsance
B lactams (and other cell wall synth inhibitors)
tetracyclines (hydrophobic, cross membrane without transporter)
mechanism under which bacteria can change expression of transport proteins for drugs
example
differential expression
E. coli makes transporter for aminoglycosides 10x less under anaerobic conditions, and not suscepible
E. coli and P. aeruginosa express around 30 efflux pumps to remove a variety of substances, including…..
tetracyclines
macrolides
TetA
tetraclycline efflux pump
H+ driven antiporter for active efflux
Resistance-nodulation cell division (RND)
ATP-driven efflux pump related to T1SS
ABC system
lactamase
degrade lactam rings
augmenters that inhibit lactamase and increase effectiveness of drug
clavulanic acid
sulbactam
lactamases that resist augmenters
zinc lactamases
part of lactamase vulnerable to augmenters
serine
kanamycin mods which reduce its action
acetylation, phosphorylation, and adenylation
Chloramphenicol acetyltransferase (CAT)
Addition of acetyl group prevents binding of chloramphenicol to 23s rRNA pepidyltransferase, and therefore exit site of ribosome is not blocked
TetX gene
codes for an NADPH-dependent oxidoreductase that forms an epoxide and inactivates the tetracycline
Tetracycline reductases
cleave a ring of drug
positive side of tetracycline enzymatic inactivators
only found in soil bacteria, not in clinical pathogens yet
TetM, TetO, TetQ
protect ribosome from tetracycline
homology with elongation factors and GTPase activity - they change shape of 16s rRNA, which decreases tetracycline binding
mecA
makes PBP2’ in MRSA, which does not bind to warhead
other species with no lactamase activity, but instead an altered PBP
S. pneumoniae
how does Enterococcus resist vanc?
modification of peptidoglycan cross-links
VRE resistance mechanism
Peptide usually ends in D-Ala-D-Ala, which vancomycin binds to, but VRE (vancomycin resistant Enterococcus) makes a D-Ala-D-lactate variant
does not bind vancomycin, so transpeptidation can proceed
function of enzymes in VRE resistance to vanc
VanH makes the lactate from pyruvate
VanA attaches D-Ala to D-lactate
VanX and VanY cleave D-Ala-D-Ala in free peptide or in the crosslinks
RNA methylases (ErmA, ErmB, etc)
confer resistance to erythromycin by methylating adenine 2058 on 23rRNA
mutation way of resisting erythromycin
adenine 2058 can mutate to guanine
allows resistance to gyrase inhibitors
mutation in A or B subunits
allows resistance to rifampin
mutation in the B-subunit of RNA polymerase
allows resistance to streptomycin
mutation in the rpsL gene for protein S12 results in a protein that does not bind streptomycin
allows resistance to metronidazole
reduced expression of flavodoxins
isoniazid mechanism
(mycobacteria)
drug activated by catalase KatG, and the product forms an adduct with carrier InhA
adduct inhibits mycolic acid synthesis
allows resistance to isoniazid
KatG is inactivated, or when the gene is deleted or expression is reduced
allows resistance to sulfa drugs
mutation in DHPS (dihydropteroate synthase) gene
allows resistance to trimethoprim
mutation in DHFR (dihydrofolate reductase) gene
