Penicillin contains a strained -lactam. The strain in the four-membered ring causes the lactam to be much more susceptible to nucleophilic attack than other amides. It is thought that the antibiotic activity of penicillin results from its ability to mimic D-alanyl-D-alanine and react with the amino group of a transpeptidase enzyme that is involved in the synthesis of bacterial cell walls. This inactivates the enzyme and actively growing bacteria die because they are unable to produce a functional cell wall.

Lactams, Penicillins and Bacterial Resistance

N

O

H

-lactam

• Show structures and electron pushing for the reaction of penicillin with the bacterial enzyme. (Represent the enzyme as enz---NH2).

penicillin

N

S

O

N

H

O

R

COO-

Why does penicillin have no effect on mammalian cells?

Bacteria that are resistant to penicillin have an enzyme present thatwe call -lactamase. As indicated in the name, this enzyme catalyzesthe hydrolysis of the -lactam ring of penicillin. The overall hydrolysisoccurs in two steps. First, the enzyme reacts with penicillin to “activate”the carbonyl.

serineresidue

In the next step of the hydrolysis, water acts as a nucleophile andattacks the “activated” carbonyl to form penicilloic acid as well asregenerate the free -lactamase.

22 Oct. 1992, Nature

NH

S

COO-

N

H

O

R

Oenz

O

“Caught in the act”

One reason that we have seen increased resistance in bacteriais the consistent overuse/misuse of penicillins and other antibiotics.We have decimated the population of “weak” bacteria (those thatdon’t have b-lactamase) and the more resistant bacteria havebeen harbored and spread throughout the environment. A 2002study by IMPART indicated that here in Rexburg, one-third of the children tested carried penicillin-resistant bacteria (S.pneumonia) in their nasal passages. A huge effort is underway toeducate the public about the use of antibiotics.

• Do penicillins fight viral infections, such as the common cold or flu?

• Why is it important to finish all of the antibiotic prescribed, evenif you are feeling better?

N

S

O

N

H

O

R

COO-

Ph

NH2

Ph

NH2

OH

NO

Cl

penicillin G

ampicillin

amoxycillin

cloxacillin

More than ten differentpenicillins are currently in use.Bacteria differ in their resistanceto penicillins. For example,ampicillin (a synthetic penicillin)is clinically effective againstbacteria that are resistant topenicillin G. The size andpolarity of the “R” group affecthow well the penicillin binds to the active site of the-lactamase enzyme.

Some newer penicillins have an additive called clavulanic acid orclavulanate. The additive provides a chemical pathway that covalentlymodifies -lactamase and makes it inactive. Augmentin is amoxicillinwith the clavulanic acid additive.

Typically, it takes a bacterial strain 15-20 years to develop resistance to a given antibiotic (survival of the fittest). Penicillinswere introduced in large quantities in the 1950s and we started tonote problems soon afterward. Pharmaceutical companies haveput billions of dollars into antibiotic research. Here are a few results:

Azithromycin (Zithromax, Z-pac)

• derived from erythromycin, differsin the N in the lactone ring• dosage is once a day, for 5 days• acts by binding to 50S ribosomalsubunit and interfering with proteinsynthesis• -lactamase production should have no effect on activity• There are bacteria that haveresistance to azithromycin, including most strains of Enterococcus faecalis