ANTIBACTERIAL CHEMOTHERAPY 🦠🪱 Flashcards
Which 4 classes of antibacterials contain B-lactam ring?
Penicillins
Cephalosporins
Monobactams
Carbapenems
Penicillins
Why do we need to decrease acid susceptibility?
The 4 membered ring (b lactam ring) is very strained, we need groups around the b lactam ring that will make the ring susceptibility to acid hydrolysis
Examples of how sensitivity to acid is overcome:
- Flucloxacillin:
The introduction of an electronic withdrawing group on the amide side chain - Amoxicillin:
Intro of a bulky group on the amide side chain
Explain the difference between
Intrinsic resistance and
Acquired resistance
Intrinsic resistance:
Natural resistance an organism has to be an antibiotic
Acquired resistance: due to chance mutation in genetic material or the acquisition of resistance genes
How do Penicillins disrupt peptidoglycan formation?
B lactams interfere with peotidoglycan formation through their interaction with the Penicillin Binding Proteins.
Penicillin MOA
Bind covalently to active site of enzyme, preventing access of peotidoglycan and attack of OH group on D-Ala
Cycloserine MOA
Resistance of cyclosterine related to?
Over production of D-Ala racemase
Resistance of Vancomycin related to?
- VRE: Vancomycin Resistant Enterococci: produces a D-Ala-D-Lactate lipase which synthesises an ester (D-Ala-D-Lac) rather than an amide (D-ALA-D-ALA)
- MRSA:
Due to plasmid (blaZ) mediated b-lactamase AND
A Chromosomal (mecA) gene which was acquired from an unknown bacterium which encodes for an altered penicillin binding protein (PBP 2a)
PBP 2a has decreased affinity for binding b lactams
Daptomycin
MOA > cell wall
Insertion of daptomucin into the lipid bilayer, facilitated by thr lipid tail, promoting weak.hydrophobic interactions with phospholipd bilayer
Resistance of Daptomycin
Point mutations in mprF and yyvG genes.
mprF enzyme influences the nature of the phospholipid content
yycG thought to be involved in cell permeability
Quinolones
MOA
Inhibit bacterial DNA gyrase snd topoisomerase IV
What do Quinolones target in Gram positive and Gram negative bacteria?
Gram positive = topoisomerase IV
Gram negative = DNA gyrase
Resistance of Quinolones?
Decreased accumulation of the quinolones in cells due to the impermeability of the membrane OR
the over expression of effluxion pumps.
Sulphonamides
Class
Moa
Antifolates= interfere with the bacterial biosynthesis of folic acid.
The sulphonamide group and a free amino group at the para position were found to be essential
How does sulphonamides prevent formation of folic acid?
Resistance of Sulphonamides
Chromosomal resistance through resistance of folP gene in E.coli, S.aureus leads to alterations in the sulphonamide binding site of the DHPS
Trimethoprim (monotrim, proloprim)
Class
Antifolate agent = DHFR inhibitor
Agents which target protein synthesis?
Chlorqmphenicol, tetracyclines, erythromycin
Chloramphenicol
MOA
Chloramphenicol binds to large ribosome subunit (50S) at the peptidyl transferable centre A site, preventing binding of the next changed tRna.
Which isomer form of Chloramphenicol is active?
Only the R,R- isomer is active
Indications of use of chloramphenicol
Treatment of meningitis in patients with b lactam allergies
Not given systemically as severe toxicity..
Used in treatment if bacterial conjunctivitis
Resistance of chloroamohenicol
Resistant to pseudomonas = due to effluxion pumps.
CAT enzyme which acetylayes chloramphenicil- so it no longer binds to the PTC a site.
Aminoglycosides (-sidal)
MOA
Bind to RNA because of interactions with phosphate backbone and hydrogen binding = causes adenines to flip out.
Causes incorporation of incorrect amino acids
Resistance of aminoglycosides
Resistance due to
Decrease uptake of increased effluxion
And
Mutations of ribosome= methylation of ribosome decreasing binding affinity of the aminoglycosides
Which antibacterials are TIME DEPENDANT?
B lactams =
Need to be in contact with PBPs for sufficient amount of time to interfere with cell wall synthesis
Macrolides
Which antibacterial is CONCENTRATION dependant?
Aminoglycosides.
Linezolid
Moa
Binds to PTC A site, disrupting the binding of the next changed trna
Linezolid
Resistance
Gram negative bacteria = resistance due to efficient bacterial effluxion pumps
Gram positive bacteria = resistance due to decreased linezolid uptake
Macrolids: erythromycin
How is acid instability of erythromycin overcome?
By use of entering costings so that drug us only released in the higher pH of the small intestines.
Macrolides
Resistance
Due to modifications to the ribosome
Resistance to streph: caused by constitutive erm.
Isoniazid
Resistance
Mycobacterium TB LINKED TO:
Mutatuons/deletions in the KatG gene regulatory region.
Resistance summary
