Antibacterial Drugs

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  • Created by: LBCW0502
  • Created on: 20-03-20 15:19
What are the general mechanisms of actions for antibacterials? (1)
Inhibition of cell metabolism - faulty wall, unable to control flow of nutrients in/out, lysis and death results e.g. beta-lactam
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What are the general mechanisms of actions for antibacterials? (2)
Targeting plasma membrane - membrane becomes permeable, resulting in cell death e.g. polymyxins
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What are the general mechanisms of actions for antibacterials? (3)
Antimetabolites - selectively target bacterial enzymes catalysis in impending bacterial growth e.g. sulphonamide
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What are the general mechanisms of actions for antibacterials? (4)
Disruption of protein synthesis - selectively blocking the synthesis of essential proteins and enzymes e.g. chloramphenicol and tetracyclines
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What are the general mechanisms of actions for antibacterials? (5)
Inhibition of nucleic acid transcription and replication - selectively target transcription and replication which impedes cell division e.g. intercalators
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Describe features of sulphonamides (sulfa drugs)
Prontosil metabolised by intestinal bacterial, sulfanilamide was the active species (first synthetic antibacterial), p-amino group is essential, aromatic ring essential, sulphonamide essential with primary/secondary nitrogen, R group can be varied
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State features of the bacterial synthesis of essential co-factor tetrahydrofolate using PABA
Involves the use of p-aminobenzoic acid and dihydropteroate synthesise. Dihydropteroate formed. L-glutamic acid used to form dihydrofolate. Dihydrofolate reductase and NADPH used to form tetrahydrofolate (process only occurs in bacteria, not mammals)
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State features of the mechanism of action (1)
Biochemical pathway utilised by bacteria to synthesis tetrahydrofolate provides one carbon unit for pyrimidine bases. Pathway is impeded, bacterial DNA synthesis stops. Sulphonamides inhibit pathway by acting as a mimic for p-aminobenzoic acid (PABA)
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State features of the mechanism of action (2)
Bacterial dihydropteroate synthesise accepts sulphonamide into active site, once bound it prevents PABA from binding. Dihydropteroate is competitively inhibited (diagram)
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State features of the mechanism of action (3)
Higher animals/mammalians synthesise tetrahydrofolate from folic acid (obtained from diet) using a different pathway. Folic acid carried across cell membrane by transport proteins. Mammalian cells lack enzyme dihydropteroate synthesise
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State features of the mechanism of action (4)
Unaffected by sulphonamides. Sulphonamides inhibit bacterial growth, they don't kill the pathogens, they don't kill the pathogens, they prevent them from multiplying
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State features of the mechanism of action (5)
Body defence hunter-killer CD8 cells eliminate the invaders. Bacteriostatic. Useful for treating infections of the eyes, mucosal membranes, GIT and urinary tract
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How does resistance against sulphonamides develop?
Bacteria synthesise more PABA. Higher concentrations of PABA can compete with sulphonamides for the target enzyme. Some bacteria have become resistant mutations of the enzyme whereby it has low affinity for the sulphonamide
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Describe features of the discovery of penicillins (1)
Alexander Fleming -St. Mary's Hospital -1928. Plate culture of Staphylococcus had been contaminated by a blue-green mould (Penicillium). Colonies of bacteria adjacent to the mould were being dissolved
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Describe features of the discovery of penicillins (2)
The mould grown in pure culture produced a substance that killed bacteria. Naming the substance penicillin.
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Describe features of the discovery of penicillins (3)
Fleming in 1929 published the results of his investigations (Brit. J. Exper. Path. 1929, 10, 226), noting that penicillin might have therapeutic value if it could be produced in quantity.
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Describe features of the discovery of penicillins (4)
First antibiotic from a natural source - industrial production of penicillin
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Describe features of penicillin biosynthesis (1)
Penicillins are synthesised by a fermentation process. L-cysteine and D-valine react to produce 6-aminopenicillinic acid (6-APA). Different COOHs are added to produce a limited number of penicillins
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Describe features of penicillin biosynthesis (2)
Semi-synthesis - 6-APA can react with COOH to produce other derivatives
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Describe the chemical structure of penicillins
Four membered β-lactam ring is fused to a five membered thiazolidine ring. Results in a non planar butterfly like structure. The β-lactam ring is unstable and is primarily responsible for the antibiotic potency. 2 Hs have cis configuration
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Describe features of a normal amide (1)
In a normal amide the lone pair of electrons on the nitrogen overlap with the carbonyl group resulting in a double bond between the nitrogen and the carbonyl carbon and a negative charge on the carbonyl oxygen
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Describe features of a normal amide (2)
This overlap has two consequences - The amide nitrogen is not basic. This renders the carbon less electrophilic and therefore less susceptible to nucleophilic attack in comparison with aldehydes, ketones and esters (N -CO, same plane)
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How is a beta lactam different to a normal amide?
Nitrogen-carbonyl are not in the same plane
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Describe features of the beta lactam ring (1)
In a bicyclic system composed of a four membered ring and a five or six membered ring results in a non planar structure and delocalisation of the electrons on the nitrogen onto the carbonyl is not possible.
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Describe features of the beta lactam ring (2)
In the four membered ring the bond angles are 90⚬ instead of 120⚬ which results in a 30⚬ strain. This also prevents the overlap of the nitrogen lone pair with the adjacent carbonyl
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Describe features of the beta lactam ring (3)
As a result the β-lactam carbonyl is much more electrophilic than a normal amide carbonyl and is susceptible to nucleophilic attack
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Describe features of the beta lactam ring (4)
The lone pair on the nitrogen is readily protonated making the β- lactam ring susceptible to ring opening in acid or base.
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Describe features of the beta lactam ring (5)
The β-lactam carbonyl is significantly more reactive than a simple amide. Normal amides are generally more stable to hydrolysis due to the delocalisation of the nitrogen lone pair onto the carbonyl
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Describe features of beta lactam stability
The β-lactam system is susceptible to ring opening under acidic an basic conditions (H3O+, HO-, nucleophiles)
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The bacterial cell wall is made up of which monomers?
N-Acetlmuramic acid, N-Acetylglucosamine (D-Gln, L-Ala)
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Describe features of the bacterial cell wall (1)
Bacterial cell wall consists of sugar and peptide - peptidoglycan. Parallel series of sugar backbone with peptides attached. Two different sugars N-acetymuramic acid (NAM) and N-acetylglucosamine (NAG). Peptide attached to NAM.
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Describe features of the bacterial cell wall (2)
Peptide chain contain D-amino acids. Bacteria contain racemase enzyme converts L-AA into D-AA, a feature not present in mammalians. Bacterial cell wall synthesis when appended peptide chains to sugar backbone are cross linked together
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Describe features of the bacterial cell wall (3)
The terminal D-Alanine in one chain is displaced by a glycine in another chain. The enzyme responsible for this cross linking is known as a transpeptidase
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Describe features of the bacterial cell wall (4)
An activated serine hydroxyl group attacks the carbon of the amide bond between the two terminal D-Alanine residues resulting in the nucleophilic displacement on one D-Alanine and the formation of a peptide chain transpeptidase complex
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Describe features of the bacterial cell wall (5)
The complex is linked by an ester bond that is readily attacked by the amino terminus of the pentaglycine chain, releasing the enzyme and completing the crosslink between two peptide chains (diagrams)
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How do penicillins interfere with the bacterial cell wall synthesis? (1)
Penicillins have a structural resemblance to D-Ala-D-Ala. Mistaken by the transpeptidase for D-Ala-D-Ala and incorporated into the active site
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How do penicillins interfere with the bacterial cell wall synthesis? (2)
Once bound the β lactam is attacked by the serine hydroxyl and ring opening occurs leaving the penicillin covalently attached to the enzyme. The bulky thiazolidine ring blocks access to the active site by either the pentaglycine or water
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How do penicillins interfere with the bacterial cell wall synthesis? (3)
As a result penicillin is irreversibly bound to the transpeptidase enzyme preventing it from functioning
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What is the mode of action of penicillin?
Mechanism. Nucleophilic attack on b-lactam carbonyl. Proton transfer. Elimination. This results in incomplete cell walls that are much more fragile and porous and eventually resulting in swelling followed by cell lysis and death.
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Describe features of penicillin G (1)
Active against Gram positive, bacilli (staphylococci, meningitis, and gonorrhoea) and Gram negative. Non-toxic. Not active on a wide range of bacteria.
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Describe features of penicillin G (2)
Ineffective when taken orally, breaks down in the acid condition of the stomach
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Describe features of penicillin G (3)
Sensitive to all known β-lactamase enzymes. Allergic reactions
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Describe features of beta-lactamase inhibitors
Streptomyces clavuligerus. Potent irreversible inhibitor of β-lactamases. Co-administered with traditional penicillins
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What are the structural requirements for beta lactamase inhibitors?
β-Lactam ring. Double bond (Z-configuration). No acylamino side-chain. Acid group at C2. (R)-stereochem at C2 and C5 (like penicillins). Variability is allowed at the 9-OH group but required (mechanism)
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What are the general properties of interest?
Acid resistant due to NH2 group (orally active). Sensitive to penicillinase (no shield). Poor absorption through gut wall. (Electron withdrawing groups, better acid stability than penicillin G, survives stomach acid, used orally)
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Describe features of methicillin (1)
First synthetic penicillin not effected by penicillinase developed in time to treat Staph. Aureus. Principle of steric shield- the presence of two methoxy groups on the ortho positions - important for shielding the lactam ring
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Describe features of methicillin (2)
No electron withdrawing group - acid sensitive. These compounds are acid resistant and penicillin resistant. Useful for staph. aureus infections
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What is the main issue with Gram negative membranes?
Repulsion between CO and gram negative membrane
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Describe features of membrane permeability (1)
Difficult for penicillins to invade gram negative bacterial cell due to the make up of the cell wall. Gram negative bacteria have a coating on the outside of the cell wall which consists of a mixture of fats sugar and protein. Coating acts as barrier
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Describe features of membrane permeability (2)
The outer surface may have an overall negative charge or a positive charge depending on the constituents triglycerides. An excess of phosphatidylglycerol would result in an overall anionic charge
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Describe features of membrane permeability (3)
An excess of lysylphosphatidylglycerol would result in an overall cation charge. Penicillin has a free carboxylic acid which if ionised would be repelled by the cell membrane
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Describe features of membrane permeability (4)
Also fatty position of the membrane may act as a barrier to polar hydrophilic penicillin molecules
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State features of broad spectrum activity
Active against Gram positive bacteria and Gram negative bacteria which do not produce penicillinase. Acid resistant due to the amino group and therefore orally active. Non-toxic. Sensitive to penicillinase
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Describe features of prodrugs
Suitable for Gram negative bacteria. Pencillins need to be made into prodrugs – esterases (hydrolysed to form ester, release carbon dioxide so penicillin is effective)
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Describe features of cephalosporins (1)
These posses structural similarities to the penicillins and have been classified by somewhat arbitrary “generations” based on features of antimicrobial activity.
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Describe features of cephalosporins (2)
Structure-Activity relationships from synthetic analogs reveal that the following. Generalisations of required functionality. Like the penicillin's, we are limited in modifications that can be made. Bicyclic. Beta-lactam
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Describe features of cephalosporins (3)
Carboxylic acid on fused 6-membered heteroatom ring. Amide side chain on β-lactam
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Describe features of glycopeptide antibiotics (1)
Broad spectrum antibiotic but toxicity limits use to antibiotic resistant staphylococcal infections resistance very rare but now emerging. E.g. ristocetin, teicoplanin. Structures of these drugs unknown till quite recently
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Describe features of glycopeptide antibiotics (2)
Glycopeptide antibiotics bind to D-ala-D-ala terminal and block peptide incorporation into cell wall
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Describe features of vancomycin resistance
Vancomycin resistant bacteria have mutated the D-ala-D-ala termination of pentapeptide to D-ala-D-Lac. This results in loss of H-bond and much lower affinity of vancomycin for this peptide in the resistant bacteria (repulsion from Os)
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Summarise features of antibacterials (1)
Mode of action of sulphonamides. Major classes of antibiotic that target cell wall synthesis in bacteria include β-lactams and glycopeptides β-lactam antibiotics consist of penicillins and cephalosporins
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Summarise features of antibacterials (2)
Penicillins and cephalosporins prepared by a combination of fermentation and synthetic modification. The β-lactam ring system shows significant chemical instability in both acidic and basic conditions.
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Summarise features of antibacterials (3)
Bacterial resistance to β-lactams has developed through presence of drug degrading enzymes known as β-lactamases. Inhibitors of these enzymes are dispensed with penicillins in order to counteract resistance.
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Summarise features of antibacterials (4)
β-lactams disrupt cell wall cross-linking through inhibiting the transpeptidase enzyme leading to cell lysis through cell wall rupture. Vancomycin binds to D-ala-D-ala unit of peptide stopping crosslinking
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Summarise features of antibacterials (5)
Resistance to vancomycin due to mutation of D-ala-D-ala to D-ala-D-lac
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