Antimicrobial chemotherapy – agents and mechanisms of action Flashcards
narrow spectrum
only affect certain organisms
broad spectrum
action against broader spectrum of microbial agents
what are most antibiotics directed against
- bacteria cell wall synthesis (peptidoglycan)
- bacteria protein synthesis (- ribosomes
- enzymes)
- bacterial nucleis acid synthesis
- DNA
- membranes
- enzymes
- metabolic pathways
when are antimicrobials useful
if the target is not present in man
if the microorganism has higher affinity for the drug than man
selective toxicity
must be highly effective against microbe but minimal toxicity in humans
- expressed by drugs therapeutic index
larger the index, after the drug for human use
what characteristics should useful antibiotics have
1) wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organism
2) non toxic to host, and without undesirable side effects
3) non allergenic to host
4) not eliminate normal flora of host
5) be able to reach part of the human body where the infection is occuring
6) inexpensive and easy to produce
7) chemically stable (have long shelf life)
8) microbial resistance is uncommon and unlikely to develop
classification of antimicrobials
1) chemical structure
- eg B lactam ring
2) target site
3) bactericidal or bacteriostatic
- cidal kill, static inhibit growth
- distinction often blurred
testing antibiotics/effectiveness
Disc diffusion on agar
- lawn of bacteria grown on the plate
- disc soaked in antibiotics placed on plate
- if sensitive, will get a clear zone surrounding disc
in liquid
MIC
MBC
testing
MIC testing
minimal inhibitory conenctraion
min concentration of antimicrobial needed to stop it growing
MBC
-minimal bactericidal concentration, min needed to kill bacteria
peptidoglycan cell wall structure
- needs to be cross linked
- amino acid cross links eg d-ala, d-glutamate
- rests on lipid bilayer
- Mae of N acetyl glucosamine
- N acetyl muramic acid
main classes of antimicrobial agents
1) B lactams
- penicillins
- cephalosporins
2) Glycopeptides
- vancomycin
- teicoplanin
3) cycloserine
- inhibits alanine racemase and D alanine Ligase
- TB treatment
B lactams and what do they mostly bind o
- bactericidal compounds
- contain a B lactam ring and inhibit normal cell wall formation
PBP (penicillin binding proteins )
PBP penicillin binding protiens
D-D transpeptidases
involved in peptidoglycan synthesis
normally present in bacterie
how does B lactam antibiotic inhibit peptidoglycan formation
NMA and NAG form cross links
- cyclosporine breaks up cross linking
vancomycin binds to alanine in the growing cross links therefore prevents peptidoglycan cross linking
penicillin bind to PBP )as it is an analogue)
inhibits formation of peptidoglycan cross links by binding b ring to enzyme DD transpeptidase
- no cross links can occur
what is vancomycin effective against
gram + organisms
binds to D alamyl D Alaine dipeptide on side chain of new subunits
prevents them being incorporated into cell wall y penicillin binding proteins (PBP)
what do tetracylines do
inhibit tRNA binding to 50s subunit( of tRNA to mRNA)
broad spectrum
incorporated into developing bone and teeth
erthromycin
blocks exit of nascent chain from ribosome
fusidic acid
binds elongation factor G (EFG)
aminoglycosides
act on 30s subuit (ribosomes)
misreading of genetic code
effective against aerobes and facultative anaerobes
not against anerobes
- given IV or IM
side effects
- nephrotoxicity
ototoxicity
macrolides
bind to 50s subunit blocking exit of nascent pp chain
bacteriostatic
- used in pts with penicillin allergy
agents that affect DNA
- DNA gyrase helps steady the DNA when it it becoming unravelled
1) Quinolones - affect DNA gyrase
2) rifamycins - affect DNA dependant RNA polymerase
3) metronidazole - strand breakage
nitrooimidazoles
e.g. metronidazole
disrupts DNA helix
only works in anerobic organisms
- activated in cell by redox enzyme pyruvate-ferredozin oxidoreductase
- in anaerobes, ferredoin is an e transported molecule that reduced (gives e- to) metronidazole (only functional in anerobic bacteria)
- this single e- transfer reduced nitro group of met. creating highly reactive anion – disrupts DNA helix
folic acid synthesis
Folic acid enzymes
- needed for amino acid synthesis
Some antibiotics can interrupt these enzymes (eg sulfonamides)
- active against gram +and – bacteria
antiobiotics bind to dihydropteroate synthetase (structural analogues)
- stops PABA turning into amino acids
how does antibiotic resistance occur
- chromosomal mutation
- some coded by plasmid DNA
Some plasmids are transmissible
antibiotic resistance definition
A organism that is not inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body after normal dosage
transfer of antibiotic resistance
Transposons
- can carry resistance genes and jump between chromosome and plasmid
1) chromosomally mediated resistance - mutant selection
- resistant bacteria can divide and grow
2) plasmid mediated resistance - spread of resistance plasmid
- donor gives plasmid to recipient bacteira (forms a transconjugant
integrons
- multiple resistant genes are sometimes organised into genetic elements
contain gene for recombination enzyme to allow insertion
why might antimicrobial agents not work
1) The target is structurally altered (by mutation)
- lower affinity for the antibacterial
- penicillin binding proteins (can change structure, therefore penicillin wont bind as much anymore)
2) the target is over produced
- dihydropteroate synthetase (PABA to aa) (bacterial target) and sulphonamide
- will overwhelm the antibiotic
3) the drug is not activated
- aerobes and metrzdazole
- antibiotic wont become active
4) drug is removed
Enzyme destruction
- B lactamase (produced by bacteria)
- aminoglycoside resistance – 3 modifying enzymes that can modify the antibiotic by changing its structure (eg phosphorylation)
Efflux
- tetracyclines, quinolones
5) drug cannot gain entry to the cell
- outer membrane barrier
- lack of transport mechanism
what can antivirals target
1) penetration/uncoating
- amantadine (influenza)
- prevent fusion of viral envelope with cell membrane
2) taking over cell machinery
Transcription
- nucleoside analogues – zidovudine, acyclovir
- zidovudine acts as a substrate for and inhibitors of viral reverse transcriptase (enzyme needed to create DNA copy of its RNA, necessary for integration into host genome)
- acyclovir – inhibits HSV DNA polymerase
Translation
- anti sense morpholinos (oligomer molecules that block target sequence in RNA by binding
3) Post translation inhibition
Protease inhibitors
- protease cleaves viral polyproteins into structural proteins required for viral replication
- protease inhibition- immature, defective viral particles
