Term
| Biosynthesis of Penicillins (AA's) |
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Definition
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Term
| Penicillin structural importance |
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Definition
B-lactam ring (Bicyclic system)
amine with carboxyl and R group (Amide essential)
H Cis stereochemistry essential
Carboxilic acid essential |
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Term
| Properties of Penicillin G |
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Definition
Active against Gram (+) bacilli and some Gram (-) cocci
Relatively Non toxic
Limited range of activity
Not orally active (iv administration)
Allergic Reaction in some patients
Inactive against Staphylococci
Resistance due to b-lactamases has developed |
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Term
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Definition
Goal:
Increase chemical stability and improve oral administration
Increase resistance to b-lactamases
Increase the range of activity |
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Term
| Penicillins - Mechanism of Action |
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Definition
Penicillin inhibits final crosslinking stage of cell wall synthesis
It reacts with the transpeptidase enzyme to form an irreversible covalent bond
Inhibition of transpeptidase leads to a weakened cell wall
Cells swell due to water entering the cell, then burst (lysis)
Penicillins inhibit the transpeptidase enzyme which is involved in the synthesis of the bacterial cell wall
The b-lactam ring is involved in the mechanism of inhibition
Penicillin becomes covalently linked to the enzyme’s active site leading to irreversible inhibition
Covalent bond formed with enzyme! |
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Term
| Penicillins Action on Gram (+) and Gram (-) Bacteria |
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Definition
Penicillins need to cross the bacterial cell wall in order to reach transpeptidase, their target enzyme
Cell walls are porous and do not provide a barrier to penicillins
The cell walls of Gram (+) bacteria are thicker than Gram (-)
Nonetheless, Gram (+) bacteria are more susceptible to penicillins, in part, because Gram (-) bacteria have a hydrophobic outer membrane not present in Gram (+) bacteria |
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Term
| Penicillins Action on Gram (-) Bacteria |
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Definition
Gram(-) bacteria possess a lipopolysaccharide outer membrane preventing access to the cell wall and Penicillins can only cross via porins in this outer membrane
High levels of transpeptidase enzyme may be present
The transpeptidase enzyme may have a low affinity for penicillins (i.e., PBP 2a for S. aureus)
b-lactamases, which render penicillins inactive, are present at high concentration in the periplasmic space
b-lactamases prone to mutations
Efflux mechanisms pump penicillins out of periplasmic space |
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Term
| Problems with Penicillin G |
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Definition
Limited range of activity
Sensitive to b-lactamases - enzymes which hydrolyze the b-lactam ring
Sensitive to stomach acids |
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Term
| Penicillin G – Acid Stability |
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Definition
Penicillin V (orally active)
Better acid stability and orally active
But sensitive to b-lactamases
Slightly less active than penicillin G
Allergy problems with some patients
Very successful semi-synthetic penicillins
e.g. ampicillin, oxacillin |
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Term
| Penicillin G - b-lactamase susceptibility |
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Definition
b-lactamases are enzymes that inactivate penicillins by opening the b-lactam ring
Transferable between bacterial strains (i.e. bacteria can acquire resistance via plasmids)
Important for Staphylococcus aureus infections in hospitals because 80% of Staph. infections in hospitals were resistant to penicillin and other antibacterial agents by 1960!
Mechanism of action for b-lactamases is identical to the mechanism of inhibition for the target enzyme but product is efficiently removed from the b-lactamase active site |
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Term
| Penicillin G - b-lactamase susceptibility Solution |
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Definition
Use steric shields!
Block access of penicillin to the active site of the enzyme by introducing bulky groups to the side chain
Size of shield is crucial to inhibit reaction of penicillins with b-lactamases, but not with the target transpeptidase enzyme |
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Term
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Definition
Methoxy groups block access to b-lactamases but not to transpeptidases
Binds less readily to transpeptidases compared to penicillin G
Lower activity compared to Pen G against Pen G sensitive bacteria
Poor activity vs. some streptococci
Inactive against Gram (-) bacteria
Poorer range of activity
Active against some penicillin G resistant strains (e.g. Staphylococcus)
Acid sensitive since there is no electron-withdrawing group
Orally inactive and cannot be given PO |
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Term
| Other Examples b-lactamase susceptibility Solution |
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Definition
Orally active and acid resistant
Resistant to b-lactamases
Active against Staphylococcus aureus
Less active than other penicillins
Inactive against Gram (-) bacteria
Nature of R & R’ influences absorption and plasma protein binding
Cloxacillin better absorbed than oxacillin
Flucloxacillin less bound to plasma protein, leading to higher levels of free drug |
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Term
| Class 1 - NH2 at the a-position |
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Definition
Ampicillin and amoxicillin
Broad Spectrum Penicillins |
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Term
| Class 2 - CO2H at the a-position (carboxypenicillins) |
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Definition
Carfecillin = prodrug for carbenicillin
Active over a wider range of Gram -ve bacteria than ampicillin
Active vs. Pseudomonas aeruginosa
Resistant to most b-lactamases
Less active against Gram (+) bacteria
Acid sensitive and must be adminsitered iv
CO2H at the a-position is ionized at blood pH |
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Term
| Class 3 - Urea group at the a-position (ureidopenicillins) |
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Definition
Administered by injection
Generally more active than carboxypenicillins against streptococci and Haemophilus species
Generally have similar activity against Gram (-) aerobic rods
Generally more active against other Gram (-) bacteria
Azlocillin is effective vs P. aeruginosa
Piperacillin can be co-administered with tazobactam |
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Term
| Properties of Cephalosporin C |
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Definition
Advantages
• Non toxic
• Lower risk of allergic reactions compared to penicillins
• More stable under acidic conditions (stomach acid)
• More stable to b‐lactamases
• Ratio of activity against Gram (‐) vs. Gram (+) bacteria is better than penicillins
Disadvantages
• Highly soluble due to polar side chain ‐ difficult to isolate and purify
• Low potency ‐ limited to the treatment of urinary tract infections where it is concentrated in the urine
• No oral absorbtion
Therefore, Cephalosporin C is useful as a lead compound for further drug
development. |
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Term
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Definition
• Similar to penicillins
• The -lactam ring is crucial to the mechanism
• The carboxylic acid at position 4 is important to binding
• The bicyclic system is important in increasing ring strain
• Stereochemistry is important
• The acetoxy substituent is important to the mechanism |
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Term
| First Generation Cephalosporins |
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Definition
• Generally possess lower activity than comparable penicillins
• Generally better range of activity than comparable penicillins
• Best activity is against Gram (+) cocci
• Useful against some Gram (‐) infections
• Useful against S. aureus and streptococcal infections when
penicillins have to be avoided
• Poorly absorbed across the gut wall (except for 3‐methyl
substituted cephalosporins)
• Most are administered by injection
• Resistance has appeared among Gram negative bacteria due to
presence of more effective ‐lactamases |
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Term
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Definition
First Generation Cephalosporins
• More active than penicillin G against some Gram (‐) bacteria
• Less likely to cause allergic reactions than penicillins
• Useful against ‐lactamase producing strains of S. aureus
• Not active against Pseudonomas aeruginosa
• Poorly absorbed from the GIT
• Administered by injection
• Metabolised to afford a free 3‐hydroxymethyl group (deacetylation)
• Metabolite is less active |
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Term
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Definition
First Generation Cephalosporins
• The pyridine ring is stable to metabolic degradation
• The pyridine ring is a good leaving group
• Exists as a zwitterion ‐ soluble in water
• Poorly absorbed through the GIT
• Administered by injection |
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Term
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Definition
First Generation Cephalosporins
• The 3‐methyl group is a poor leaving group
• Methyl group is bad for activity but helps oral absorption
• Can be administered orally
• The hydrophilic amino group at the ‐carbon of the side chain helps to
compensate for the loss of activity due to the 3‐methyl substituent |
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Term
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Definition
2nd Generation Cephalosporins
• Isolated from a culture of Streptomyces clavuligerus
• First ‐lactam to be isolated from a bacterial source
• Modifications carried out on the 7‐acylamino side chain
• Resistant to esterases due to the urethane substituent |
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Term
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Definition
2nd Generation Cephalosporins
• Broader spectrum of activity than most first generation cephalosporins
• Greater resistance to ‐lactamase enzymes
• The 7‐methoxy group may act as a steric blocker
• The urethane group is stable to metabolism |
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Term
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Definition
2nd Generation Cephalosporins
Oximinocephalosporins:
• Much greater stability against some ‐lactamases
• Resistant to esterases due to the urethane group
• Wide spectrum of activity
• Useful against organisms that have gained resistance to penicillin
• Not active against P. aeruginosa
• Used clinically against respiratory infections |
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Term
| 3rd Generation Cephalosporins |
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Definition
3rd Generation Cephalosporins
Oximinocephalosporins:
• Aminothiazole ring enhances penetration of cephalosporins across the outer
membrane of Gram (‐) bacteria
• May also increase affinity for the transpeptidase enzyme
• Good activity against Gram (‐) bacteria
• Variable activity against Gram (+) cocci
• Variable activity against P. aeruginosa
• Lack of activity against MRSA
• Generally reserved for troublesome infections |
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Term
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Definition
3rd Generation Cephalosporins
Oximinocephalosporins:
• Injectable cephalosporin
• Excellent activity vs. P. aeruginosa and other Gram (‐) bacteria
• Can cross the blood brain barrier
• Used to treat meningitis |
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Term
| 4th Generation Cephalosporins |
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Definition
Oximinocephalosporins:
• Zwitterionic compounds
• Enhanced ability to cross the outer membrane of Gram (‐) bacteria
• Good affinity for the transpeptidase enzyme
• Low affinity for some ‐lactamases
• Active against Gram (+) cocci and a broad array of Gram (‐) bacteria
• Active against P. aeruginosa |
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Term
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Definition
5th Generation Cephalosporins
(Telfaro)
• Approved by the FDA in 2010
• Active against (MRSA)
• Active against Gram (+) bacteria
• Under investigation for community‐acquired pneumonia and complicated skin
infections |
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Term
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Definition
• Isolated from Streptomyces cattleya
• Potent and wide range of activity vs Gram (+) and Gram (-) bacteria
• Active against Pseudomonas aeruginosa
• Low toxicity
• High resistance to -lactamases
• Poor stability in solution (ten times less stable than Pen G) |
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Term
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Definition
Carbapenem
• Approved by the FDA in 2007
• An ultra‐broad spectrum injectable antibiotic effective against
gram (+) and gram (‐) bacteria
• Particularly active against Pseudomonas aeruginosa
• Not active against MRSA |
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Term
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Definition
• Monocyclic ‐lactam ring
• Moderately active in vitro against narrow group of Gram (‐) bacteria
• Activevs. Pseusomonas aeruginosa
• Inactive vs. Gram (+) bacteria
• Different spectrum of activity from penicillins
• Thought to operate by a different mechanism from penicillins
• Lowtoxicity |
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Term
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Definition
Mono‐bactam
• Administered i.v.
• Can be used for patients with allergies to penicillins and
cephalosporins
• No activity vs. Gram (+) or anaerobic bacteria
• Active vs. Gram (‐) aerobic bacteria |
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Term
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Definition
Clavulanic acid
• Isolated from Streptomyces clavuligerus
• Weak, unimportant antibacterial activity
• Powerful irreversible inhibitor of b‐lactamases ‐ suicide substrate
• Used as a sentry drug for ampicillin
• Augmentin = ampicillin + clavulanic acid
• Allows less ampicillin per dose and an increased activity spectrum
• Timentin = ticarcillin + clavulanic acid |
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Term
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Definition
• Suicide substrates for b‐lactamase enzymes
• Sulbactam has a broader spectrum of activity against b‐lactamases
than clavulanic acid, but is less potent
• Unasyn = ampicillin + sulbactam |
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Term
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Definition
• Suicide substrates for b‐lactamase enzymes
• Tazobactam has a broader spectrum of activity against b‐lactamases
than clavulanic acid, and has similar potency
• Tazocin or Zosyn = piperacillin + tazobactam |
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Term
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Definition
Cyclic Lipopeptides
• New class of antibiotic isolated from Streptomyces roseosporus
• Disrupts multiple aspects of bacterial cell membrane function
• Inserts into the cell membrane and aggregation of daptomycin alters the
curvature of the membrane, which creates holes that leak ions.
• Often effective against resistant gram (+) infections |
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