patrick-lactams

1. © Oxford University Press, 2013
THIENAMYCIN
MONOBACTAMS
β-LACTAMASE INHIBITORS
Patrick: An Introduction
to Medicinal Chemistry 6e
Chapter 19

2. © Oxford University Press, 2013
1. Thienamycin
•Isolated from Streptomyces cattleya
•Potent and wide range of activity vs Gram +ve and Gram -ve bacteria
•Active vs. Pseudomonas aeruginosa
•Low toxicity
•High resistance to b-lactamases
•Poor stability in solution (ten times less stable than Pen G)
Carbapenam nucleus
Acylamino side
chain absent
Plays a role
in b-lactamase
resistance
Merck 1976
Opposite
stereochemistry
to penicillins
Carbon
Double bond leading to high
ring strain and an increase in
b-lactam ring reactivity

3. © Oxford University Press, 2013
1. Thienamycin
Thienamycin analogues used in the clinic
Imipenem
Ertapenem(2002)
Meropenem

4. © Oxford University Press, 2013
2. Monobactams
Nocardicins (Fujisawa 1975)
•Monocyclic b-lactam ring
•Moderately active in vitro vs narrow group of Gram -ve bacteria
•Active vs. Pseusomonas aeruginosa
•Inactive vs. Gram +ve bacteria
•Different spectrum of activity from penicillins
•Thought to operate by a different mechanism from penicillins
•Low toxicity
Nocardicin A

5. © Oxford University Press, 2013
2. Monobactams
Clinically useful monobactam
•Administered by intravenous injection
•Can be used for patients with allergies to penicillins and
cephalosporins
•No activity vs. Gram +ve or anaerobic bacteria
•Active vs. Gram -ve aerobic bacteria
Aztreonam

6. © Oxford University Press, 2013
3. b-Lactamase Inhibitors
Clavulanic acid (Beechams 1976)
•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
Oxazolidine ring
No acylamino
side chain
b-Lactam
Sulphur replaced
by oxygen
9
2
5
3
4
1
7
6

7. © Oxford University Press, 2013
3
CH2OH
CO2H
O
O
HN
O
NH
H
OH
NH
2
1
H
CH2OH
CO2H
O
N
O
Clavulanic acid - mechanism of action
3. b-Lactamase Inhibitors
2
N H
2
CH2OH
O
HN
O
O
CO2H
B
a
s
e
H
4
H
CH2OH
CO2H
O
O
H2N
O
NH
5
NH
CH
O
HC
O
Irreversibly blocked

8. © Oxford University Press, 2013
Penicillanic acid sulphone derivatives
•Suicide substrates for b-lactamase enzymes
•Sulbactam has a broader spectrum of activity vs b-lactamases
than clavulanic acid, but is less potent
•Unasyn = ampicillin + sulbactam
•Tazobactam has a broader spectrum of activity vs b-lactamases
than clavulanic acid, and has similar potency
•Tazocin or Zosyn = piperacillin + tazobactam
3. b-Lactamase Inhibitors
Sulbactam Tazobactam

9. © Oxford University Press, 2013
Diazabicyclooctanes
•Suicide substrates for b-lactamase enzymes
•Avibactam approved in 2015
•Relebactam was undergoing clinical trials in 2017
•No b-lactam ring
•Slow, reversible inhibitors
•React with serine residue
3. b-Lactamase Inhibitors
Avibactam Relebactam

10. © Oxford University Press, 2013
Diazabicyclooctanes
3. b-Lactamase Inhibitors
H+
OH
Ser
b-Lactamase enzyme
O
Ser
b-Lactamase enzyme