Sulfazecin, SAR, Aztreonam, Structure Similarity to beta lactams, antibacterial, resistant to β-lactamases, Gram-positive or anaerobic bacteria

1. MONOBACTAMS
Dr. Shilpa Sudhakar Harak
Asst. Prof., Pharm. Chem.,
GES Sir Dr. M. S. Gosavi College of Pharmaceutical Education and
Research, Nashik

2. Beta-lactam
 A beta-lactam (β-lactam) ring is a four-membered lactam.
 A lactam is a cyclic amide, and beta-lactams are named
so because the nitrogen atom is attached to the β-carbon
atom relative to the carbonyl.
 The simplest β-lactam possible is 2-azetidinone.

3. Types of Lactam

4. Basic ring
nomenclature

5. Sulfazecin
 First isolated useful monobactam antibiotics from
saprophytic soil bacteria
 Weakly active as an antibacterial agent
 Highly resistant to β-lactamases.
 SAR studies eventually led to the development of
aztreonam

6. Sulfazecin
 SAR studies eventually led to the development of aztreonam
 3-methoxy group - responsible for β-lactamase stability in the
series,
 contributed to the low antibacterial potency & poor chemical
stability of these antibiotics.
 4-methyl group –
 increases stability to β-lactamases and
 increases activity against Gram-negative bacteria
 potency against Gram-positive bacteria decreases.
 4,4-Gem-dimethyl substitution –
 slight decrease in antibacterial potency after oral
administration.

7. Aztreonam
 Monocyclic β-lactam antibiotic
 Natural molecules served as the inspiration for the synthesis
 Totally synthetic parenteral antibiotic
 Exclusively active towards gram-negative microorganisms,
 Inactivates some β-lactamases.
 MOA similar to that of the penicillins, cephalosporins, and
carbapenems,
 Has strong affinity for PBP-3, producing filamentous cells as a
consequence.

8. Aztreonam
Structure Similarity:
 The C3 sulfamic acid moiety attached to the β-lactam ring similar to
ceftazidime.
 The sulfur at N1 is similar to C-2 carboxyl group of β-lactam antibiotics to
confuse the PBPs.
 The strongly EW group - sulfamic acid group makes the β-lactam bond more
vulnerable to hydrolysis.
 The monobactams demonstrate that a fused ring is not essential for
antibiotic activity.
 The α-oriented methyl group at C-2 is associated with the stability of
aztreonam toward β-lactamases.

9. Ceftazidime Vs Aztreonam
Ceftazidime

10. Tigemonam
 Newer monobactam that is orally active.
 It is highly resistant to β-lactamases.
 The antibacterial spectrum of activity resembles that of aztreonam.
 It is very active against the Enterobacteriaceae, including E. coli,
Klebsiella, Proteus, Citrobacter, Serratia and Enterobacter spp.
 It also exhibits good potency against H. influenzae and N.
gonorrhoeae.
 Tigemonam is not active against Gram-positive or anaerobic bacteria
and is inactive against P. aerugi
 The oral absorption of tigemonam is excellent.
 It could become a valuable agent for the oral treatment of UTI and
other non–life-threatening infections caused by beta-lactamase–
producing Gram-negative bacteria.

11. For more details on
 Mode of Action pharmacophores
 responsible for activity of monobactams
 refer slideshare presentation for Penicillin Antibiotics @
 https://www.slideshare.net/shilpa1980/penicillin-237643170