antibiotics Flashcards
examples of toxicity
aminoglycoside - kidney damage and neurotoxicity in inner ear ( deafness and loss of balance) affect sensory hai cells
penicillin - hypersensitivity
fluoroquinolone - photosensitivity
biosynthesis of peptidoglycan
production of ADP - NAM
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
fosfomycin
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
D-cycloserine
structural analogue of D-ala
inhibit L ala racemase, Dalanyl Dalanine synthetase, ligase
drug resistant TB - second line
bacitracin
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
transpeptidases
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
beta lactam drugs
penicillin
cephalosporin
monobactam
carbapenem - has differentsteochemical config of substituents to penicillin and cephalosporin
penicillin and cephalosporin has thiazolidine ring
action of beta lactam
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
vancomycin
bind the terminal ala ala of peptidoglycan in network of 5 hydrogen bonds
inhibit transpeptidase
susceptible to osmotic pressure - cell lysis
antibiotics that act on protein synthesis
macrolides tetracycline chloramphenicol aminoglycoside fusidic acid
act on 30s
tetracycline
spectinomycin - polyketide antibiotics
streptomycin + kanamycine = aminoglycosides
tetracycline
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.
erythromycin
+ expanded spectrum 14 members
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
clarithromycin
azithromycin
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
macrolide + lincosamide
competitive relationship
lincosamide = direct peptidyltransferase inhibitors
mutation in 23s rRna affect binding of macrolides, lincoasmide, streptogramin B
clindamycin
both A and P sites of peptidotransferase centre
complete with loaded tRNA
co -crystal structures suggest overlap in binding sites.
chloramphenicol
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
fusidic acid
bind and inhibit elongation factor G
prevent translocation
narrow spectrum
for staphylococcal infections
G+
eye and skin infections
synercid
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
aminoglycoside
gentamycin + streptomycin
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
drugs acting on DNA replication expression and repair
fluoroquinolones
rifampicin
dauomycin
fluoroquinolone
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
DNA gyrase FQ complex
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
Levofloxacin
3rd generation FQ
improved against strepto pneumoniae
Aminocoumarins
low water solubility unsuitable for oral low activity against gram -ve target Gyr B drug resistance
rifampicin
+ other derivatives of rifamicin
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)
dsDNA binding
non covalent:
daunomycin
bleomycin
covalent:
aziridines - mitomycin C
daunomycin
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
Bleomycin
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
mitomycin C
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
folic acid synthesis
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
sulfamethoxazole
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
trimethoprim
inhibit dihydrofolate reductase
DHFR has enough structural differences from mammalian ones so selectivity can be achieved
co-trimoxazole
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 )
acting on membrane
valinomycin gramicidin A polymixin daptomycin ( gluconazole)
valinomycin
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
nigericin
monensin
K+ - nigericin
na+ - monensin
H+ antiporters
gramicidin 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
polymixin
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.
daptomycin
cyclic lipopeptidolactone
in complex with Ca2+
some of its effects through membrane seeking behaviour - -
polyene
antifungal
nystatin
amphotericin B
form ion channels in membrane
bind ergosterol
against cryptococcus, candida and aspergillus
triazoles - synthetic
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
