Current Topics in Chemistry - Bruice

Dr. Glaser's "Chemistry is in the News"
To Accompany Bruice, Organic Chemistry, 3/e.
Chapter 16. Carbonyl Compounds I: Reactions of Carboxylic Acids and Their Derivatives with Oxygen and Nitrogen Nucleophiles

For each of the following questions, please refer to the following article:

DRUG-RESISTANT SALMONELLA SPREADING, RESEARCHERS WARN
by Damaris Christensen (Medical Tribune News Service, May 7, 1998)

Editorial Comments

Measures to curb the overuse of antibiotics are urgently needed. Medical organisations around the world warn that the world is in danger of losing its most important pharmacological weapon against disease. Jeremy Laurence recently wrote that "millions of tons of antibiotics had been released on the planet in the last 50 years" and he described the result with the statement "the world was now bathed in a dilute solution of the drugs". But instead of destroying all microbes they had become resistant.

Stuart Levy, director of the center for drug resistance at Tufts University, Boston, recently said: "Multidrug-resistant bacteria are increasing, patients are failing therapy and some are dying. That would have been unheard of ten years or even five years ago in some cases.

Penicillin is our oldest weapon against bacteria. Penicillin was discovered serendipitously by Alexander Fleming and its germicidal activity had previously also been noticed by Lord Joseph Lister (the poor fellow who missed his best opportunity for a major discovery). Fleming did recognize the significance of his discovery but he was too limited in his resources and unable to pursue human trials. It was only in the late 1930s that other scientists found a way to mass-produce penicillin. Eventually, in 1945, Sir Alexander Fleming, Sir Ernst Boris Chain and Lord Howard Walter Florey were awarded the Nobel Price in Medicine for the discovery of penicillin and its curative effects in various infectious diseases.

Today, there are more than ten different penicillins in clinical use. Let's reflect a bit on what these penicillins have in common and how they differ and let's take a look at their mode of action and the mode of their deactivation. To begin with, use the ChemFinder and take a look at the structure of "penicillin" itself.

Pertinent Text References
Chapter 16. Carbonyl Compounds I: Reactions of Carboxylic Acids and Their Derivatives with Oxygen and Nitrogen Nucleophiles.
Chapter 16. Box on "The Discovery of Penicillin".
Chapter 16. Box on "Penicillin and Drug Resistance".
Chapter 16. Box on "Penicillin in Clinical Use".

Questions

Question 1: Define the terms "lacton" and lactam". Provide a specific example for each type of compound and state how they are formed.

Answer 1: Lactones are cyclic esters, they are formed by intramolecular esterification of hydroxy-substituted carboxylic acids. Specific example: Esterification of gamma-hydroxyhexanoic acid. Lactams are cyclic amides, they are formed by intramolecular amid formation of amino-substituted carboxylic acids. Specific example: Amide formation of gamma-aminohexanoic acid.

Question 2: What structural features are common to all penicillins and in what way do the penicillin varieties differ? Be specific about the difference between penicillin itself, penicillin G and amoxicillin.

Answer 2: See Bruice 3/e, Chapter 16, p. 713. The R group attached to the alpha-position of the beta-lactam ring differs. The R group in penicillin G is Ph-CH₂- and the R group in amoxicillin is 4-HO-Ph-CH(NH₂)-. The ChemFinder structure shows the R group of penicillin.

Question 3: Briefly explain the term "beta-lactamase" and explain, using structural formulas, the mechanism of action of beta-lactamase on penicillin.

Answer 3: See Bruice 3/e, Chapter 16, p. 712. A "beta-lactamase" is any molecule that catalyzes the destruction of a beta-lactam. Typically, the beta-lactamase contains a primary alcohol function which attacks the lactam.

Question 4: Explain how penicillin acts an antibiotic. State what enzyme is being inactivated and show the structures of the active and of the active enzyme.

Answer 4: See Bruice 3/e, Chapter 16, p. 712.

Chemistry & Society.
Question 5: It seems that the one most important step that should be taken to contain the problem of increasing drug resistance consists in limiting the use of antibiotics in livestock solely to treating disease, just as health organizations have called on doctors to stop prescribing antibiotics unnecessarily. Why has this step not been taken?