Amoxicillin Amoxil

Structural Formula

Ball-and-Stick Model

Structural Formula

Ball-and-Stick Model

: Carbon = Hydrogen S = Oxygen M = Nitrogen = Sulfur

Year of discovery: 1972; Year of introduction: 1979 (GlaxoSmithKline); Drug category: (3-Lactam/penicillin; Main uses: For the treatment of bacterial infections, bronchitis, pneumonia, urinary tract infections, gonorrhea, blood infections, typhoid fever and the eradication of Helicobacteria pylori in the gut; Other brand names: Isimoxin, Ospamox; Related drugs: Augmentin (Amoxicillin + Clavulanic acid), Unasyn (Ampicillin + Sulbactam), Piperacillin (Pipracil).

It was discovered serendipitously by Alexander Fleming in 1928 that a fungus of the Penicillum family produces a material that has powerful antimicrobial activity. For that discovery, he received the Nobel Prize in Medicine in 1945 along with H.W. Florey and E.B. Chain. The latter two followed up on Fleming's finding years later and their studies led to the successful application of penicillin to humans in 1943. Because many soldiers in World War II were dying of wound-related infections, a massive wartime program was undertaken by the Allies on the development of Fleming's antibiotic, which became known as penicillin. A consortium of US and UK scientists in universities and in industry worked together under the government wartime research program to determine ways to purify penicillin, determine the chemical structure and find a method for mass production. That effort succeeded, and by 1944 sufficient penicillin G had been made for routine use by the military.

Penicillin belongs to the class of drugs known as (3-lactams which all feature a four-membered cyclic amide (shown at left). The penicillin nucleus (called 6-aminopenicillanic acid or 6-APA, shown in red) contains an amino-substituted p-lactam ring sharing a common edge with the five-membered thiazolidine ring. The penicillin nucleus is essential for antibiotic activity, whereas the side chains (shown in blue) determine the pharmacological properties.1

The production of structurally diverse natural penicillins became possible when it was discovered that the chemical composition of the fermentation medium influenced the nature of the side chain group. For example the addition of phenylacetic acid or phenoxyacetic acid to the fermentation medium resulted in the production of penicillin G and penicillin V, respectively.2

phenylacetic acid

Penicillum chrysogenium o' V O

6-APA

Semisynthetic Penicillins r>

Thiazolidine phenoxyacetic acid

Penicillum chrysogeniurr

VH H

Yry*

Penicillin G

VH H

Penicillin V

Later, the mass production of the side chain-free 6-aminopenicillanic acid allowed the assembly of penicillin derivatives by chemical synthesis (semisynthetic penicillin derivatives) which led to compounds with improved potency and bioavailability that are still in use today.

Amoxicillin, discovered in 1972, is an orally active aminopenicillin that is effective against both Gram-positive and Gramnegative bacteria. Penicillins, including amoxicillin, work by inhibiting the growth of the bacterial cell wall that is essential for the survival of microorganisms. Bacterial cell walls consist of peptide-sugar copolymers that are cross-linked by bridges. This essential cross-linking reaction is catalyzed by the enzyme transpeptidase, which is inhibited by penicillins. However, over time bacteria become resistant by expressing enzymes that degrade penicillins. The most common mechanism is the production of [3-lactamases that cleave the amide bond in the four-membered ring and render the drug inactive. An X-ray picture of the deactivated amoxicillin (red) bound covalently to Ser64 (cyan) of the enzyme (3-lactamase is shown below.4

in the kidney. The imlpenem/cilastatin sodium combination is sold as Primaxin™. It is effective against a number of serious Gramnegative infections, especially those involving cephalosporin-resistant strains.

Imipenem

CI coc

Imipenem

Cilastatin sodium

In connection with the search for new antibiotics of microbial origin, a structurally-related |B-lactam natural product, clavulanic acid, was discovered. While it has negligible antimicrobial activity, clavulanic acid was found to be an irreversible inhibitor of (3-lactamases. Shortly afterwards, Glaxo marketed the combination of amoxicillin and clavulanic acid as Augmentin. This became a major antibiotic because of its effectiveness against |3-lactamase-producing resistant strains. Another inhibitor of (3-lactamase, sulbactam, was discovered at Pfizer, which introduced a formulation of sulbactam with ampicillin (Unasyn and Ampictam).

CHj CH,

Clavulanic acid o

Sulbactam

The synthesis of penicillin derivatives that do not have a sulfur atom in the five-membered ring led to a family of broad-spectrum antibiotics, the carbapenems, that are active against both Gram-positive and Gramnegative bacteria. Carbapenems are not cleaved by several classes of (3-lactamases and consequently are useful against many (3-lactamase-producing, penicillin-resistant strains. Imipenem, the most widely used carbapenem, was developed at Merck and sold in combination with cilastatin, a dipeptidase inhibitor, since imipenem alone is rapidly deactivated by the dipeptidase enzyme

Monocyclic |3-lactam antibiotics (monobac-tams) are stable to many (but not all) [3-lactamases. The best known member of this family is aztreonam (Azactam™, Squibb) which is active only against Gram-negative bacteria Aztreonam is generally well-tolerated and is especially useful in patients who are allergic to penicillin. The electron-withdrawing group S03H (green) on the nitrogen atom is important, since it increases the reactivity of the [3-lactam ring towards cleavage. In the absence of this group monobactams are not active enough to inhibit the transpeptidase enzyme. It was by screening a library of monobactams that the cholesterol-absorption inhibitor ezetimibe was discovered (see page 65).

Aztreonam (AzactamlM) Ezetimibe (ZetiaiM)

Penicillins are biosynthesized by an iron-containing enzyme from the tripeptide cysteinyl-valine aminoadipate, as shown in the equation below. This elegant design requires enzymatic catalysis and cannot be effected by purely chemical reaction conditions.

Cysteinyl-valine aminoadipate

I Penicillin iSynthase

1. Drug Interactions in Infectious Diseases (2nd Edition, Humana Press. 2005); 255-287; 2. Antimicrob. Agents 2005, 113-162; 3. Int. J. Antimicrob. Agents 2007, 29, 3-8; 4 Chem. Biol. 2002, 9, 971-980 (1ll9); Refs. p. 174

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