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Lactams, Penicillins and Bacterial Resistance

Lactams, Penicillins and Bacterial Resistance. b -lactam. penicillin. Show structures and electron pushing for the reaction of penicillin with the bacterial enzyme. (Represent the enzyme as enz---NH2). Why does penicillin have no effect on mammalian cells?.

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Lactams, Penicillins and Bacterial Resistance

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  1. Lactams, Penicillins and Bacterial Resistance b-lactam penicillin • Show structures and electron pushing for the reaction of penicillin with the bacterial enzyme. • (Represent the enzyme as enz---NH2).

  2. Why does penicillin have no effect on mammalian cells?

  3. Bacteria that are resistant to penicillin have an enzyme present that we call b-lactamase. As indicated in the name, this enzyme catalyzes the hydrolysis of the b-lactam ring of penicillin. The overall hydrolysis occurs in two steps. First, the enzyme reacts with penicillin to “activate” the carbonyl. serine residue

  4. In the next step of the hydrolysis, water acts as a nucleophile and attacks the “activated” carbonyl to form penicilloic acid as well as regenerate the free b-lactamase.

  5. “Caught in the act” 22 Oct. 1992, Nature

  6. One reason that we have seen increased resistance in bacteria • is the consistent overuse/misuse of penicillins and other antibiotics. • We have decimated the population of “weak” bacteria (those that • don’t have b-lactamase) and the more resistant bacteria have • been harbored and spread throughout the environment. A 2002 • study 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 to • educate 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, even • if you are feeling better?

  7. More than ten different penicillins are currently in use. Bacteria differ in their resistance to penicillins. For example, ampicillin (a synthetic penicillin) is clinically effective against bacteria that are resistant to penicillin G. The size and polarity of the “R” group affect how well the penicillin binds to the active site of the b-lactamase enzyme.

  8. Some newer penicillins have an additive called clavulanic acid or clavulanate. The additive provides a chemical pathway that covalently modifies b-lactamase and makes it inactive. Augmentin is amoxicillin with the clavulanic acid additive.

  9. Typically, it takes a bacterial strain 15-20 years to develop resistance to a given antibiotic (survival of the fittest). Penicillins were introduced in large quantities in the 1950s and we started to note problems soon afterward. Pharmaceutical companies have put billions of dollars into antibiotic research. Here are a few results: • derived from erythromycin, differs • in the N in the lactone ring • dosage is once a day, for 5 days • acts by binding to 50S ribosomal • subunit and interfering with protein • synthesis • b-lactamase production should • have no effect on activity • There are bacteria that have • resistance to azithromycin, • including most strains of • Enterococcus faecalis Azithromycin (Zithromax, Z-pac)

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