penicillins week 26 costello Flashcards
Penicillins are — agents which inhibit…
antibacterial
bacterial cell wall synthesis
Side-chain of penicillin depends on the —/— present in the — medium
carboxylic acid
fermentation
Name the 2 rings in penicillins:
B-lactam ring
Thiazolodine ring
Penicillin G:
Active against…
Toxic or Non-toxic?
Limited range of —
In terms of administration, It is not — active, must be —.
It is sensitive to which bacterial enzyme?
Some patients cannot take as they are ….
Inactive vs …
Gram +ve bacilli Non-toxic activity orally injected B-lactamase allergic Staphylococci
3 drug development aims of penicillin G:
Increase stability for oral administration
Increase resistance to b-lactamases
increase range of activity
Nutrient broth can generate the bulk of the penicillin structure which is called… /// — Can not be made this way, they are synthesised elsewhere. The — side chain, also referred to as the — differs with different —.
6-aminopenicillanic acid R-groups Acyl R-group Penicillins
SAR conclusions for penicillins:
Amide + COOH groups involved in —
COOH binds as a — ion
Activity of the B-lactam ring is related to the — involved in the ring.
—/— system increases b-lactam ring —
binding carboxylate strain Bicyclic system strain
Mechanism of bacterial cell-wall synthesis:
— catalyses the cross-linking between — and — in the cell wall for increased stability.
DD-Transpeptidase
Glycine
D-alanine
penicillin binds — to transpeptidase active site leading to — inhibition. This inhibition causes — to enter the cell and eventually it — and — (bursts)
covalently irreversible water swells lyses
The bicyclic ring is called a — ring
Penam
An alternative theory of penicillin mechanism is that it mimics the — portion of the cell wall
D-alanine D-alanine
Penicillin may also act as an umbrella inhibitor. This means that it may bind somewhere close to the —/— of the enzyme which still enables it to stop the — of the cell wall
active site
catabolism
Penicillin fermentation:
The —/— is varied in the — medium
Limited to — acids at the — position.
This process is tedious and —
carboxylic acid fermentation carboxylic alpha slow
Analogue penicillin preparation by total synthesis:
Only yields about -%
This process is also very —
:
1
impractical
Semi-synthetic procedures use — occurring structures as starting material for — synthesis
naturally
analogue
How do you hydrolyse the side chain of a sensitive molecule without affecting the b-lactam ring?
Activate the side chain first to make it more reactive
Antibiotic resistance:
Mechanisms:
- drug inactivation by —
- Alteration of —
- Alternative metabolic —
- Reduced drug — mechanisms
Exacerbating factors:
- Failure to — course of antibiotics; exposure of — to — concentrations of antibiotic increases — of bacteria.
- Veterinary use: exposure to — bacteria via —.
B-lactamases target pathway accumulation finish bacteria sub-optimal resistance resistant meat
3 problems with penicillin G:
Sensitive to stomach acid
not resistant to b-lactamase
limited range of activity
Factors affecting acid sensitivity of Penicillin:
Ring strain- Because of position of —/— in beta-lactam ring, the amide is very weak because the lone-pair in b-lactam ring can not — itself in the same way it does in normal —. It can not rotate and — with empty —
lone-pair reorientate amides overlap orbitals
Factors affecting acid sensitivity in penicillin:
A very reactive B-lactam — group.
Nitrogen in B-lactam ring does not behave like a — amide. Interaction of the lone-pair on the — is not possible with the — group, this results in the — group being very reactive
carbonyl tertiary nitrogen carbonyl carbonyl
One factor affecting the acid sensitivity of penicillin is the participation of the —/—/—.
Acyl Side chain
Strategy to defeat acid sensitivity:
Vary the Acyl side chain to make it electron-withdrawing to reduce the nucleophilicity of the carbonyl oxygen.
Penicillin V: Better acid --- Is active when administered --- Sensitive to --- slightly less active than --- Some patients have --- problems
stability orally b-lactamases Penicillin G allergy
Name 2 semi-synthetic penicillins:
Ampicillin
Oxacillin
Beta-Lactamases:
Allows — to become resistant to —
Mechanism for lactamases is identical to mechanism of inhibition for —/—
bacteria
penicillins
target enzymes
Sensitivity to B-lactamases:
- Penicllins use — shields.
- Blocks access of penicillin to — by adding —/— to the side chain.
- — of shield is crucial to inhibit reaction of penicillin with —., but not with the target — enzyme
steric B-lactamase bulky groups size B-lactamases transpeptidase
Methicillin:
The — group blocks access to the —, but not to the —.
It has a — range of activity.
It is acid sensitive because…
Inactive when administered —, it must be —
methoxy b-lactamase transpeptidase poorer there is no electron withdrawing group orally injected
Oxacillin:
Orally active and — resistant because of — and —/— R-group. Resistant to most —. Active vs —/—
Less/more active than other penicillins?
Acid bulky electron withdrawing staphylococcus aureus Less
Broad spectrum, class 1 penicillins have a — group at the — position. Give 2 examples of these..
NH2
alpha
ampicillin
amoxicillin
Carbapenems: Originally developed from --- isolated from ---/--- found in soil last resort against ---/--- they have low --- High resistance to --- poor stability in --- has the opposite --- to penicillins in the ---/--- Have a --- nucleus The --- side chain in absent
Thienamycin streptomyces cattleya E.coli infections toxicity b-lactamases solution stereochemistry b-lactam ring carbapenem acylamino
What is NDM-1?
Which 2 types of antibiotics are effective against NDM-1?
For antibiotic 1, why is it not ideal?
For antibiotic 2, why is it not ideal?
New Delhi metallo Beta-lactamase Colistin Tigecycline quite toxic not effective against all infections.
Monobactams:
The b-lactam ring is —
moderately active in vitro against — range of —/—
Inactive vs — bacteria
Low —
thought to act by different — than —-
Active vs —
Monocyclic narrow gram -ve bacteria gram +ve toxicity mechanism, penicillins Pseusomonas aeruginosa
Aztreonam: Administered how? can be used if patient is... No activity against --- or ---- Active against ---, --- bacteria The only commonly available ---
Intravenous allergic to penicillins gram +ve or anaerobic gram -ve aerobic monobactam
B-lactamase inhibitors: CLAVULANIC ACID
No — side chain
B-lactam ring still present, but with —- ring which has — instead of —.
A powerful and — inhibitor of —
It is known as a —/—
Used as a — drug for —
What is the name for the ampicillin/clavulanic acid combo?
Allows for less — needed per dose and increases the spectrum for —
acylamino oxazolidine oxygen sulphur irreversible b-lactamase suicide substrate sentry ampicillin Augmentin ampicillin activity
Suicide inhibition:
When an — binds irreversibly to a — analogue forming and irreversible — .
Inhibitor binds to —/— of enzyme where it’s modified to produce a — group that reacts — to form a stable —/— complex
enzyme substrate complex active site reactive irreversibly inhibitor/enzyme
