Beta-lactams and penicillin

In Orgo II the other day, we discussed a super interesting biochemical application of beta-lactams moieties. Lactams are cyclic amides (also known as lactone amides) that are most often found as either six-membered rings, called delta-lactams, 5-membered rings, called gamma-lactams, or four-membered rings, called beta-lactams. Here’s a good representation of these from Wikipedia:

The beta-lactams, or four-membered lactams, are extremely reactive since four-membered rings are very sterically unfavorable. Because of this inherent reactivity, these beta-lactams can be inserted into molecules to add a reactive site to the molecule. Commonly, these beta-lactams are used in antibiotics, such as penicillin, shown below.

The beta-lactam in penicillin reacts with the hydroxyl groups of in or near the active site of bacterial enzymes. Specifically, it reacts with the bacterial enzymes, called transpeptidases, that cross link the bacterial cell wall together (NAM-NAG-, etc, just like we reviewed before!). Shown below is a representation of penicillin reacting and blocking the active site of one of these transpeptidase membrane building enzymes in bacteria by acylating the enzyme.

The reactivity of these beta-lactam moieties allow the antibiotic to bind to the transpeptidase membrane building enzymes, also known as penicillin binding proteins, in the bacteria. This therefore impairs their ability to correctly cross link the membrane and the membrane falls apart. Furthermore, resistance to these beta-lactam agents occurs when a bacterium can produce a penicillin binding enzyme that has an active site with a conformational change that does not allow beta-lactam binding to occur. Bacteria can also produce beta-lactamases that bind with the penicillin before it is able to bind with the penicillin binding proteins at all! Cool, huh?