B. Cephalosporins, monobactams and carbapenems

β-lactamase inhibitors
 Almost all have weak antibacterial activity.
 Important in combination with penicillins sensitive to
β-lactamase degradation.
 Clavulanic acid is the first one of this class.
Natural product from streptomyces.
Has a powerful and irreversible inhibition of βlactamase enzymes because it will covalently bind to
two positions in the active site.
Normally used in combination with
amoxicillin and other β-lactamase
sensitive penicillins
SAR for β-lactamase inhibitors
 β-lactam ring is essential.
 The enol ether have a rule in binding.
 The elkene moiety should have Z configuration which
is much more active than the E isomer.
 No substitution at C6.
 R stereochemistry at C3.
 Carboxylic acid at C3 is essential.
 The first agent discovered was cephalosporin C, obtained
from the fungus cephalosporium acremonium.
 1/1000 the antibacterial activity of penicillin G.
 Has the same mechanism of action as penicillins (inhibits
cell wall cross linking).
 Has greater stability toward acid and β-lactamase.
SAR of cephalosporins
 The bicyclic system is essential.
 The carboxylic acid at C4 is essential.
 Acylamino group at C7 is essential.
 Acetyloxy group at C3 is important and act as a leaving
group when the molecule binds to transpeptidase.
Synthesis of Cephalosporins
 Unlike 6-APA, 7ACA was difficult to isolate and purify.
 Instead, 7ACA was synthesized from cephalosporin C
as follows
Generation Cephalosporins
 Have lower activity than penicillin but they have
broader spectrum action.
 Still susceptible to β-lactamase degradation.
 Steric shield helped to improve stability toward β-
lactamase degradation but proved to reduce
antibacterial activity.
Generation Cephalosporins
 Have the good leaving group, pyridinium ion.. This
improved activity.
 This group is not hydrolysable compared to the acetyloxy
group found in cephalothin.
 Poorly absorbed from the gut because it will be ionized all
the time.
 Only given parenterally.
Generation Cephalosporins
 They have methoxy group at C7 which make them
active against the resistant strains.
 They have a carbamate group at C3 that increase
stability toward hydrolysis compared to the acetyloxy
group found in 1st generation derivatives.
Generation Cephalosporins
 Other agents are the oximinocephalosporins:
 Have the iminomethoxy group at the α-carbon in the
acyl side chain, this increased stability toward βlactamase.
Generation Cephalosporins
 Here the aminothiazole ring has replaced the furan
ring of cefuroxime:
 This enhanced the penetration through the outer
membrane of gram –ve bacteria,
 Increase the affinity for transpeptidase.
 Not recommended as first
line therapy to prevent the
rapid development of resistance.
Generation Cephalosporins
 Cefdinir (Omnicef®):
 It has a broad spectrum activity.
 More active on gram –ve bacterial
infections such as respiratory, skin and soft tissues
 Estimated oral bioavailability is 20-25% (WHY?).
 LogP = 0.02
 pKa = 3.27
Generation Cephalosporins
 They have a positively charged group at C3 which become a
good leaving group during the binding with
 They are more polar than the old generation, better
penetration for the outer membrane of gram –ve bacteria.
 More stable toward β-lactamase.
New generation Cephalosporins
5th generation cephalosporin (2008).
Only given IV (Why?).
Resistant to staphylococcal β-lactamase (Why?).
activity against methicillin-resistant S. aureus, penicillinresistant S. pneumoniae, P. aeruginosa, and Enterococci.
New generation Cephalosporins
3rd generation cephalosporin.
has very specific activity against P. aeruginosa.
limited activity against Gram-positive bacteria and
anaerobic bacteria.
Is not clinically used nowadays (difficult to purify during
New generation Cephalosporins
5th generation cephalosporins.
It retains the activity of later generation cephalosporins
having broad spectrum activity against Gram -ve and gram
+ve bacteria especially on resistant strains.
Approved for clinical use in USA in 2010.
Still in clinical trials (phase III).
New generation Cephalosporins
3rd generation cephalosporins.
It is mainly active on gram –ve bacteria.
Only available as intramuscular injections.
LogP = - 0.87
New generation Cephalosporins
Predict its pharmacokinetic and activity profile?
 No thiazolidine or dihydrothiazine ring.
 They have two strained rings which decrease the
chemical stability as well as acid stability.
 The inverse stereochemistry at C6 and the presence of
hydroxyl group increase stability toward β-lactamase
 They have broad spectrum activity.
 It has a limited activity against gram +ve bacteria.
 Because it does not have the fused ring system, Aztreonam
is believed to have different mechanism of action..
 highly polar structure which reduce the oral
bioavailability… it is recommended to be given parenterally

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