Living Textbook MC610

Select Topic:

Monobactams

First discovered in 1981, these monocyclic antibiotics are produced by several bacterial species.

The first agent, Sulfazethin showed poor antibacterial properties and chemical instability. Upon removing the methoxy group, stability improved, but the agent was ß-lactamase sensitive.

Various side chains were tried, and finally the use of ceftazidime's side chain gave a compound with high activity and broad spectrum that included pseudomonas sp. In addition placing a 4-alpha methyl group gave better ß-lactamase resistance.

So combining all three changes gave rise to Azotreonam, a totally synthetic compound which was the first monobactam clinically used. It is effective against most Gram negative bacteria including pseudomonas sp., but no appreciable activity against Gram positive bacteria.

It has the same mechanism of action as all ß-lactams, binding PBP-3.

Used parenterally against severe infections caused by Gram negative bacteria.

Unlike Penicillins and Cephalosporins, Monobactams have no stress on the ß-lactam ring (No second ring) and the molecule is planner, so tautomerization of the amide bond is possible. So how do we account for its activity?

The presence of an electron withdrawing group (such as the SO 3- group) is essential to prevent tautomerization and facilitate ß-lactam ring opening. The stronger the electron withdrawing ability of the substitute, the more active the Monobactam. It also seems that the SO3- group makes the molecule a better fit for the enzyme, being in same spot as 3-carboxylic acid (size of S).