Chemotherapy L2 Flashcards
4 major targets for antibiotics?
(i) cell wall biosynthesis,
(ii) protein biosynthesis,
(iii) DNA replication, repair and expression and
(iv) folate coenzyme biosynthesis
Gram-positive and gram-negative bacteria both have a __________ layer as part of their cell wall structure
Gram-positive and gram-negative bacteria both have a peptidoglycan (PG) layer as part of their cell wall structure
The PG layer is generally substantially thicker and multi-layered in gram-____ bacteria
The PG layer is generally substantially thicker and multi-layered in gram-positive bacteria (
In addition, the PG layer in gram-positive bacteria has ….. associated with it.
In addition, the PG layer in gram-positive bacteria has polymers of teichoic acids associated with it.
T or f
Many of the antibiotics that affect the biosynthesis of the bacterial cell wall inhibit enzymes or sequester substrates involved in PG assembly and cross-linking.
T
describe the steps of peptidoglycan (3)
describe teh synthesis of UDP N-acetylmuramyl-pentapeptide
(stage 1 of the synthesis of peptidoglycan (cytoplasm))
UTP is bound covalently to N- acetylglucosamine to form UDP N-acetylglucosamine. A three-carbon unit from phosphoenolpyruvate and three amino acids are then added to form a UDP N-acetyl muramyl-tripeptide. In step 2, a D-alanyl-D-alanine dipeptide is joined to produce UDP N-acetyl muramyl pentapeptide.
linking together one UDP N- acetylmuramyl-pentapeptide to one UDP N-acetylglucosamine
linked to bactoprenol phosphate
D- cycloserine
how does it wokr?
Exposure of the organism to the antibiotic D- cycloserine prevents the formation of the pentapeptide, because it is a structural analogue of D-alanine, and hence, inhibits the enzymes L-alanine racemase (which converts L-alanine into D-alanine), D-alanyl-D-alanine synthetase, and possibly also the ligase that connects the D-alanyl-D-alanine unit to the muramyl-tripeptide.
fow does fosfomycin wokr?
Fosfomycin is another antibiotic that inhibits cell wall biosynthesis at this stage. It inhibits pyruvyl transferase, the enzyme that catalyses the transfer of the phosphoenolpyruvate group to UDP N-acetylglucosamine in the production of UDP N-acetyl muramyl-tripeptide.
what is lipid 2?
describe how lipid 2 is incorporated into peptidoglycan
On the outside surface the basic repeating units for PG synthesis are then put together to form a long PG polymer. For this purpose, the repeating unit is separated from the bactoprenol carrier, yielding bactoprenol pyrophosphate, and attached to existing PG by the enzyme peptidoglycan transglycosylase (step 6). In addition, PG polymers become cross- linked to each other by means of the enzyme peptidoglycan transpeptidase.
how does bacitracin work?
As bacitracin forms a very tight complex with Mg2+ and bactoprenol pyrophosphate, this cyclic peptide antibiotic inhibits the regeneration of the lipid carrier (bactoprenol), and hence, the biosynthesis of PG.
how do Penicillins, cephalosporins and other b-lactam antibiotics work?
Penicillins, cephalosporins and other b-lactam antibiotics inhibit the transpeptidation reaction that generates cross-links between PG strands
actions of transpeptidase and transglycosylase?
difference in cross lniks between gram + and gram - bacteria
gram - = short cross links
gram + = long cross links (hence the thicker peptidoglycan is looser)
descibe the mechanism of action for penicillin
Transpeptidase forms a covalent intermediate with its peptide substrate, and with penicillin…
how doe vancomycin act?
The glycopeptide antibiotic vancomycin binds to pentapeptidyl tails in the PG repeating unit terminating in D-Ala4-D-Ala5
This substrate sequestration shuts down transpeptidation by making the D-Ala-D-Ala terminus unavailable to the transpeptidase enzyme
4 groups of beta lactam antibiotics?
Basic structures of four groups of β-lactam antibiotics. T
he structures illustrate the β- lactam ring (marked B), which is present in all drugs in this class, and the thiazolidine ring (marked A), which is present in penicillins and cephalosporins.
Various substituents are added at R1, R2, R3, to produce agents with different properties.
In carbapenems, the stereochemical configuration of substituents on the β-lactam ring is different from those in penicillin and cephalosporin molecules.
Structure of major classes of antibiotics that target 30S subunit of ribosome (preventing bacterial protein syntehsis)
what do tetracycliuns inhibit?
protein synthesis
how do tetracyclins inhibit protein synthesis?
The tetracyclines reversibly bind to the 30S ribosome and inhibit the entry of aminoacyl-tRNA into the acceptor site (A-site) on the 70S ribosome.
give some examples of tetracyclins?
tetracycline, minocycline and doxycycline
describe tetracyclins spectrum of activiy?
and 2 things theyre first line for?
Broad spectrum; first-line drugs against Mycoplasma sp. (intracellular bacterium) and Vibrio cholerae.
Destruction of normal intestinal flora results in increased secondary infections
problems with tetracyclins?
bind to calium and magnesium
causes staining of tooth enamel and impairs the structure of bone
“Tetracycline should be taken on an empty stomach, at least 1 hour before or 2 hours after meals or snacks. Drink a full glass of water with each dose of tetracycline. Do not take tetracycline with food, especially dairy products such as milk, yogurt, cheese, and ice cream.”
Aminoglycosides - are they bacteriostatic?
no bacteriocidal
howd o Aminoglycosides work?
The aminoglycosides bind to the 30S ribosomal subunit and freeze the 30S pre-initiation complex (30S su + mRNA + fmet-tRNA) so that no further initiation can occur.
The aminoglycosides also slow down protein synthesis that has already been initiated and induce misreading of the mRNA (hence bactericidal).
problems with aminoglycosides?
Streptomycin is nephrotoxic and ototoxic.
Gentamycin less toxic
spectrum of aminoglycosides?
Narrow spectrum; Active uptake in aerobic Gram-negative rods.
Also active against some Gram(+) bacteriav
Use porins for uptake (as theyre abit sugery)
do aminoglycosides show post antibiotic effect?
whts meant by PAE?
yes
Only occurs for specific drug-bacterium combinations
Aminoglycosides show PAE for Gram(-) bacteria because these antibiotics are accumulated in the cell by active transporters in the plasma membrane
Structure of major classes of antibiotics that target 50S subunit of ribosome?
name them
chloramphenicol, clindamycin, linezolid, and the macrolides erythromycin, clarithromycin, azithromycin, and tylosin
describe erythrmycin
- Naturally occuring macrolide
- derived from Streptomyces erythreus
- narrow spectrum (gram +)
problems with erythromycin?
acid lability, narrow spectrum (Gram +), short elimination half-life
Erythromycin has a similar antibacterial spectrum as ______ and is a suitable second-line drug for patients allergic to ______.
Erythromycin has a similar antibacterial spectrum as penicillin G and is a suitable second-line drug for patients allergic to penicillin.
describe the 2nd generation macrolides ?
structural derivertives of erythromycin:
- clarithromycin
- azithromycin
- Extended spectrum of activity
- Improved PK properties – better bioavailability, better tissue penetration, prolonged half-lives
advatnages of 2nd generation macrolides?
ØExtended spectrum of activity
ØImproved PK properties – better bioavailability, better tissue penetration, prolonged half-lives
paromomycin - whats it usually used to treat>
parasitic disease
how does spectinomycin work?
spectinomycin interferes with the function of elongation factor G during translocation.
Paramomycin and streptomycin - how do they wokr?
Paramomycin and streptomycin bind to the 30S subunit near the A site for aminoacyl-tRNA binding, in distinct areas; in fact their binding is cooperative. In their presence, there is a disruption in decoding and translational accuracy, resulting in a decrease in the fidelity of translation.
how does tetracylcin work? and whats its binding site?
- binds to rRNA on 30S subunit
- interactions of the Mg2+ ion cause it to bind
- doesnt block initial binding of aminoacyl-tRNA
- the subsequent rotation of aminoacyl- tRNA into the A site would be blocked by tetracycline.
- The aminoacyl-tRNA would then be prematurely released, terminating that cycle without peptide bond formation.
how does erythromycin and the expanded-spectrum 14-membered macrolide antibiotics clarithromycin and roxithromycin work?
bind at the entrance to the polypeptide export tunnel of the 50S subunit and interact with the 23S rRNA, allowing about a six- to eight-oligopeptidyl-tRNA build-up before elongation is blocked and prematurely terminated.
is ther considerable interaction at the binding sites on the 50S subunit?
yes.
macrolides are competitive with lincosamide antibiotics (such as lincomycin) that are direct peptidyltransferase inhibitors.
mutations in the 23S RNA simultaneously alter the binding of macrolides, lincosamides and streptogramin B family members, suggesting the partial physical overlap of binding sites of these antibiotics
Chloramphenicol is an ______ drug
Chloramphenicol is an emergency drug
what limits chloramphenicols use?
(restricts it to emergency use:)
Although an effective broad-spectrum antibiotic, its use is limited by serious toxicity (bone marrow suppression).
chloramphenicol supresses what?
bone marrow
chlormaphenicol is the major treatment for what?
Major use in treatment of bacterial meningitis caused by Haemophilus influenzae or Neisseria meningitidis, or if organism is unknown. It is also specially used for Rikettsia (typhus).
how does chloramphenicol work?
- binds the 50S subunit
- It is known that chloramphenicol blocks aminoacyl-tRNA interaction with the A site of the peptidyl transferase centre, and that is indeed where chloramphenicol is bound
what interesting about this image?
Overlap with the binding sites for clindamycin and chloramphenicol as well as the A-site and P-site tRNAs
T or F
Chloramphenicol and clindamycin have overlapping binding sites on the 50S subunit
T
fusidic acid blocks what in bacteria?
protein synthesis
how doesFusidic acid block protein synthesis
inhibits elongation factor G (GTP dependent factor required for peptide translocation).
describe the spectrum of fusidic acid?
narrow spectrum: skin and eye infections by Gram(+) bacteria (eye droplets).
are protein synthesis inhibitors bad for side effects?
which protein synthesis inhibitor is better in this respect
many protein synthesis inhibitors have toxic side effects (aminoglycosides, tetracyclines e.a.).
Fusidic acid is better in that respect.
which antibiotics?
Competition with aminoacyl-tRNA binding at A-site:
Competition with aminoacyl-tRNA binding at A-site: tetracycline
which antibiotic?
Freezing of the 30S pre-initiation complex (30S subunit + mRNA + fmet-tRNA):.?
Freezing of the 30S pre-initiation complex (30S subunit + mRNA + fmet-tRNA): aminoglycosides (streptomycin)
which antibiotic?
Abnormal codon:anticodon leads to misreading of mRNA: _________?
Abnormal codon:anticodon leads to misreading of mRNA: aminoglycosides
which antibiotic?
Inhibition of transpeptidation: ______?
Inhibition of transpeptidation: chloramphenicol
which antibiotic?
Inhibition of peptide translocation:…..?
Inhibition of peptide translocation:
erythromycin (exit tunnel),
fusidic acid (inhibits elongation factor G)
many antibiotics which inhibit protein synthesis are bacterio………?
bacteriostatic.
since bacteria cannot control their environment - theyre used to not being able to transcribe proteins for a while.
bacteria have evolved stress response mechanisms to survive periods of starvation.
which class of antibiotic which blocks bacterial protein synthesis is bacteriocidal?
aminoglycoside antibiotics:
As the presence of aminoglycoside streptomycin (or the newer, less toxic gentamycin) decreases the fidelity of mRNA translation = wrongly folded proteins, for eg membrane proteins = leaking of membrane and cell death
Among the macrolides, erythromycin may be bacteriostatic or bactericidal, the nature of the response depending on the bacterial species, the drug concentration and the bacterial density.
fat
mamba
