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antibiotics Flashcards

1
Q

examples of toxicity

A

aminoglycoside - kidney damage and neurotoxicity in inner ear ( deafness and loss of balance) affect sensory hai cells

penicillin - hypersensitivity

fluoroquinolone - photosensitivity

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2
Q

biosynthesis of peptidoglycan

production of ADP - NAM

A

PEP + UDP- n-acetylglucosamine
by pyruyl transferase
to UDP-N-acetyl - muramyl tripeptide

+ D-Glu, L-Lys, L-ala

+ D-ala, D-ala ( L-alanine racemase, D-alanyl-Dalanine synthetase, ligase that connect it to NAM

UDP- NAM + UPD-NAG

linked to bactoprenol or C55 undecaprenyl phosphate

flipase?

used to peptidoglycan peptidase

dephosphorylation of bactoprenol pyrophosphate

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3
Q

fosfomycin

A

inhibit the committed step of peptidoglycan synthesis
mimics PEP
inhibit pyruvyl transferase
alkylates an active site cysteine ie Cys115 in E.Coli

UTIs
high specicity low toxicity
high rate of resistance

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4
Q

D-cycloserine

A

structural analogue of D-ala
inhibit L ala racemase, Dalanyl Dalanine synthetase, ligase

drug resistant TB - second line

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5
Q

bacitracin

A

form tight complex with Mg2+ and bactoprenol pyrophophate
prevent recycling of bactoprenol
prevent biosynthesis of PG

localised skin and eye infections
can cause kidney damage if use systemically

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6
Q

transpeptidases

A

serine hydrolase
attack of amide bond between 4-5ala
adduct collapeses to form acyl-O-Ser enzyme with release of D-ala as free amino acid

the intermediate has the glycan-tetrapeptidyl moiety as the transiently linked acyl group

transferred to DAP-NH2 in E.Coli = hence a short rigid peptidoglycan even though gram -ve

transferred to L-Lysin- (L-glycine)5 in S.aureus - long crosslink more fluidity

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7
Q

beta lactam drugs

A

penicillin
cephalosporin
monobactam
carbapenem - has differentsteochemical config of substituents to penicillin and cephalosporin

penicillin and cephalosporin has thiazolidine ring

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8
Q

action of beta lactam

A

mistake the drug as PG chain with terminal ala-ala
long term inactivation

the active site of transpeptidase enzyme added to th 4 ring lactam carbonyl and gives an acyl enzyme in which the beta lactam ring has opened.

since water is excluded from active site of enzyme - the dhydrolysis of covalent penicilloyl enzyme is slow

cell wall autolysin break down cell wall - normally to remodel the cell wall during growth

only proliferating cells in whcih autolysins are active are affected.

beta lactamase break open the ring

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9
Q

vancomycin

A

bind the terminal ala ala of peptidoglycan in network of 5 hydrogen bonds
inhibit transpeptidase

susceptible to osmotic pressure - cell lysis

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10
Q

antibiotics that act on protein synthesis

A 
macrolides 
tetracycline
chloramphenicol 
aminoglycoside 
fusidic acid
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11
Q

act on 30s

A

tetracycline
spectinomycin - polyketide antibiotics
streptomycin + kanamycine = aminoglycosides

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12
Q

tetracycline

A

minocycline, doxycycline
bacteriostatic - bacteria have mechanisms to cope with imbalance of protein synthesis

broad spectrum first line against mycoplasma sp., Vibrio cholerae

side effects: destruction of normal gut flora increase 2o infections, staining and impairment of the structure of teeth ( binding to Ca in bones and teeth )

Ca2+ and Mg2+ binding has consequence for PK/ PD
ie dairy products reduce absorption except minocycline.

reversibly bind 30s ribosome
groove 20A wide 7A deep

Oxygens of internucleotide PD links in 16s RNA form electrostatic interactions, guided through Mg2+ to the bottom of the edge of tetracycline.

inhibit rotation of aminoacyl tRNA into the A site, causes premature release of tRNAand peptide bond not formed.

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13
Q

erythromycin

+ expanded spectrum 14 members

A

macrolides

streptomyces erythreus
short elimination half life
narrow spectrum G+
acid lability issues

clarithromycin, rixothromycin

bind entrance of export tunnel of 50s subunit

depend on conc, bacterial species, bacterial density, bacteriocidal or bacteriostatic

side effects general - abdominal discomfort, diarrhoea, nausea and vomiting

resistance
methylation of A2058 in 50s subunit

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14
Q

clarithromycin

azithromycin

A

extended spectrum of macrolide
improved pK properties - better bioavailability, better tissue penetration, prolonged half lives

use: respiratory tract infection,s mild to moderate skin and soft tissue
otitis media

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15
Q

macrolide + lincosamide

A

competitive relationship
lincosamide = direct peptidyltransferase inhibitors

mutation in 23s rRna affect binding of macrolides, lincoasmide, streptogramin B

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16
Q

clindamycin

A

both A and P sites of peptidotransferase centre
complete with loaded tRNA
co -crystal structures suggest overlap in binding sites.

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17
Q

chloramphenicol

A

bacteriostatic
emergency drug
bacterial meningitis
neisseria mengitidis, haemophilus influenzae, rikettsia ( typhus)

effective broad spectrum
serious toxicity - bone marrow suppression

bind 50s subunit
inhibit aminoacyl tRNA binding at A site

overlap with binding of clindamycin

acute porphyrias

superficial eye drops

18
Q

fusidic acid

A

bind and inhibit elongation factor G
prevent translocation

narrow spectrum
for staphylococcal infections

G+
eye and skin infections

19
Q

synercid

A

syngergistic non ribosomal peptide combination ( quinupristin + dalfopristin)
block polypeptide translocation by binding to 23S rRNA
partially overlapping with those targetted by macrolides

dalfopristin binds 23S and changes its conformation - enhancing binding of quinupristin and inhibit peptidyl transfer

quinupristin binds to nearby site on the 50s ribosomal subunit and prevent elongation of the polypeptide.

vancomycin resistant enterococcus faecium
staphylococci infections

20
Q

aminoglycoside

gentamycin + streptomycin

A

bactericidal
streptomycin
gentamycin - less toxic

kanamycin - freezes the 30s pre initiation complex

streptomycin - decreases fidelity of translation target 30s ribosome- abnormal codon anticodon interaction ( nephrotoxicity and ototoxicity )

used against g-ve pseudonomas, proteus

most streptococci ( gram + ve ) resistant as gentamycine cannot penetrate cell. 
however penicillina dn aminoglycoside have synergistic effects on some streptococci.

when this happens in membrane proteins - affect permeability of the membrane
leak of small molecules then larger molecules - eventually whole proteins from bacterial cell before aminoglycoside induced death

21
Q

drugs acting on DNA replication expression and repair

A

fluoroquinolones
rifampicin
dauomycin

22
Q

fluoroquinolone

A

EXPENSIVE

synthetic, broad spectrum
bactericidal
UTIs

ciprofloxacin - against Bacillus anthrax

psuedomonas infection in respiratory tract infections in patients with cystic fibrosis

gram+ve and -ve
UTI, osteomyelitis, community acquired pneumonia, gastroenteritis

gatifloxacin - improved against G+ve pathogens

targets Topo II
topo IV - only carry out ATP dependent relaxation of DNA
= more potent catenase than DNA gyrase

affect double strand cleavage re-ligation equilibrium

killing effect from block of downstream progression of replication fork

DNA repair mechanisms recruited by DSB - when fail turns on signalling pathways that rapidly lead to rapid directed cell death - apoptosis

23
Q

DNA gyrase FQ complex

A

interact with both GyrA and GyrB

GyrB = DNA binding domain

Gyr A = ATPase

bind to cysteine in A under oxidised conditions
crosslinks by thiol reactive FQ

L

24
Q

Levofloxacin

A

3rd generation FQ

improved against strepto pneumoniae

25
Q

Aminocoumarins

A 
low water solubility 
unsuitable for oral 
low activity against gram -ve 
target Gyr B 
drug resistance
26
Q

rifampicin

+ other derivatives of rifamicin

A

bactericidal

tight binding to allosteric site on beta subunit of dna dependent RNA polymerase ( 1:1)

bind the DNA/RNA tunnel and block the synthesis at the di/tri stage

affect initiation
but not progressing synthesis

TB drug

inhibit fungal RNA polymerase in vitro ( not in vivo)

27
Q

dsDNA binding

A

non covalent:
daunomycin
bleomycin

covalent:
aziridines - mitomycin C

28
Q

daunomycin

A

streptomyces peuceticus

intercalation -with ethidium and actinomycin D

insert in between the base pair stacks

based on preliminary unwinding of the double helix

affects dimension of the local major and minor grooves

affect template DNA with DNA pol

RNA pol and transcription factors

inhibit replication and transcription

29
Q

Bleomycin

A

non covalent
reversible

peptide polyketide

metal chelating glycopeptide
bind in minor groove and by intercalation

bind Cu II in plasma
taken up by transporter
reduced to bleomycin Cu I

produce superoxide and hydroxy radicals - induce SSBs, DSBs in DNA.

toxic in lungs - high O2

especially toxic to gram +ve bacteria

30
Q

mitomycin C

A

Aziridine
alkylating agent
cross link betwen G and G transposition

topical use in glaucoma sugery to prevent scarring

does not act on naked DNA - needs to be reduced in cell

forms carbonium radicals during cross linking reaction

attack N7 of guanine - exposed

31
Q

folic acid synthesis

A

7,8 dihydropterin pyrophosphate + para-aminobenzoate
= 7.8 dihydropteroate

+ glutamate
7, 8 dihydrofolate =

5678 tetrahydrofolate

used as methyl carrier co enzyme in biosynthesis of dTMP and hence DNA
also in many other enzymes

32
Q

sulfamethoxazole

A

p - aminobenzoate analogue

inhibit 7 8 dihydropteroate synthase
DHPS - absent in mammals

cells accumulate dihydrofoltae - the pool will take a long time to deplete

slow and ineffective when used alone

analogue is sulfadiazine

33
Q

trimethoprim

A

inhibit dihydrofolate reductase

DHFR has enough structural differences from mammalian ones so selectivity can be achieved

34
Q

co-trimoxazole

A

sulfamethoxazole
trimethoprim
synergy
reduced toxicity

withdrawn in the uK due to implications in Stevens- Johnson syndrome - sometimes fatal allergic reaction.

related drugs used in pneumocystic infections ( pheumocystitic carinii ) in AIDS patients, toxoplasma and plasmodium spp ( malaria )

35
Q

acting on membrane

A 
valinomycin 
gramicidin A 
polymixin 
daptomycin 
( gluconazole)
36
Q

valinomycin

A

ion carrier
from streptomyces spp
Rb>K>Na>Li

l lactate, l valine, D hydroxyisovalerate D valine
forming a circular structure

precisely coordinates dehydrated K+ to carbonyl groups in hydrophilic interior of valinomycin ( 10^4 greater affinity than Na+ )

electroneutral
K+ uniporter
alters MP

37
Q

nigericin

monensin

A

K+ - nigericin
na+ - monensin

H+ antiporters

38
Q

gramicidin A

A

hyodrphobic linear polypeptide antibiotic 15 amino acids and carboxyterminal ethanolamine

dimerise

transmembrane ion channel allowing passive diffusion of molecules with diameter up to 5A

39
Q

polymixin

A

Colistin
cyclic amphipatic protein
cyclic peptide and hyodrophic tail.
net charge of 5+

has many L-DAB

Associate with -ve phosphate head of bilayer

bind g+ and make leaky membrane

use was stopped due to toxicity
used now for multidrug resistant G - ie pseudomonas aeruginosa.

aggregate into michelle like substancs when bind lidids affecting their permeability

all lipopeptide antibiotics proposed to have some membrane penetration properties.

40
Q

daptomycin

A

cyclic lipopeptidolactone
in complex with Ca2+
some of its effects through membrane seeking behaviour - -

41
Q

polyene

A

antifungal
nystatin
amphotericin B
form ion channels in membrane

bind ergosterol

against cryptococcus, candida and aspergillus

42
Q

triazoles - synthetic

A

antifungal
inhibit enzymes in ergosterol synthesis

fluconazole- thelet’s foot + vaginal candidiasis
imidazoles - ie micronazole

depletion affects fluidity of membrane
- affect permeability and membrane associated enzymes

ketonazole in shampoo

chemo (7 decks)

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