β-LACTAM ANTIBIOTICS
THIENAMYCIN
MONOBACTAMS
β-LACTAM INHIBITORS
1. Thienamycin
Acylamino side
chain absent
OH
Plays a role
in ß-lactamase
resistance
Opposite
stereochemistry
to penicillins
Merck 1976
Carbon
H
H
H3C
NH3
S
N
O
CO2
Double bond leading to
high ring strain and an increase
in b-lactam ring reactivity
Carbapenam nucleus
•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)
1. Thienamycin
Thienamycin analogues used in the clinic
H OH
Me
O
H OH
Me
NH
HN
H
N
CO2
H
H
O
O
C
N
Me
Meropenem
S
N
Me
H
N
Me
O
H OH
Imipenem
S
CO2
H
H
N
Me
O
C
N
H
Ertapenem(2002)
S
N
CO2
CO2
2. Monobactams
Nocardicins (Fujisawa 1975)
HO2C
D
HC
H2N
O
CH2
N
OH
C
H
N
C
CH2
H
OH
O
Nocardicin A
N
C
O
H
CO2H
•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
2. Monobactams
Clinically useful monobactam
Me
N
H2N
Me
O
H
N
N
S
CO2H
O
O
Me
Aztreonam
N
SO3-
•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
3. b-Lactamase Inhibitors
Clavulanic acid (Beechams 1976)
Sulphur replaced by O
No acylamino
side chain
H
9
O
5
6
7
N
1
OH
4
3
2
H
O
H
CO2H
b-Lactam
Oxazolidine ring
•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
3. b-Lactamase Inhibitors
Clavulanic acid - mechanism of action
1
NH
2
NH
2
O
CH2OH
2
O
N
O
H
CH2OH
HN
O
H
Base
CO2H
O
OH
3
CO2H
4
O
5
CH2OH
H2N
NH
NH
O
HN
O
O
H
CH
H
CH2OH
HC
O
CO2H
NH
CO2H
O
O
O
Irreversibly blocked
3. b-Lactamase Inhibitors
Penicillanic acid sulfone derivatives
O
S
O
6
5
7
N
O
O
S
Me
1
6
2
Me
3
CO2 Na
Sulbactam
O
N
Me
N
3
N
O
N
CO2
Tazobactam
•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
COMPULSORY READING FROM TEXTBOOK – WILSON AND GISVOLD
• PAGES - 274 – 278
•
EXAMPLES: CLAVULANATE POTASSIUM, SULBACTAM,
TAZOBACTAM, THIENAMYCIN, MEROPENEM [PAGES 274 – 278]
COMPULSORY READING FROM TEXTBOOK – PATRICK
•
THE ENTIRE SECTION ON b – LACTAMASE INHIBITORS
AND ANTIBIOTICS IN CHAPTER 19