6 Case study: cephalosporin antibiotics

In this week’s case study you will learn about the history and development of cephalosporin antibiotics. You might recall from previous weeks that these are broad-spectrum, bactericidal, ß-lactam antibiotics.

The story starts in Italy where the first cephalosporin, cephalosporin C, was discovered in cultures of C. acremonium found growing in a sewer near the Sardinian coast. You can find out more in Activity 5.

Activity 5 The history of cephalosporins

Allow about 15 minutes

First, listen to the following audio recording about the discovery and development of cephalosporins.

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Audio 1 Discovery and development of cephalosporins.

Transcript

Now answer the following questions, based on the audio recording.

1. Who discovered the first cephalosporin?

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2. What antibacterial activity did a crude extract derived from C. acremonium demonstrate?

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3. Which chemical structure is described as the ‘nucleus’ of cephalosporins and why is it significant?

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4. What is the difference between the first and later generations of cephalosporins in terms of their spectrum of activity?

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Answer

1. The Italian scientist Giuseppe Brotzu (1895–1976).
2. The extract could suppress the growth of Salmonella typhi and Staphylococcus aureus.
3. The starting point for all cephalosporin derivatives (generations) is 7-aminocephalosporic acid, or 7-ACA.
4. First-generation cephalosporins are only effective against Gram-positive bacteria. The later generations have increasing activity against Gram-negative bacteria.

Guy Newton and Edward Abraham were interested in cephalosporin C because, although it was a weak antibiotic, it was resistant to ß-lactamase.This is the bacterial enzyme and resistance factor that can inactivate ß-lactam antibiotics.

The drive behind the experiments that resulted in 7-aminocephalosporic acid (7-ACA) was to create a chemically modified derivative of cephalosporin C with enhanced antibacterial activity and intact ß-lactamase resistance. Newton and Abraham found that modifying cephalosporin C could effect the desired change, as long as the 7-ACA ‘nucleus’ containing the ß-lactam ring remained intact (Figure 7).

Figure 7 Synthesis of 7-ACA by Newton and Abraham (Wright et al., 2014). You do not need to know the chemical structures in this figure.

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To this day, all cephalosporins are semi-synthetic and are derived from cephalosporin C via 7-ACA. Batch fermentation of the natural antibiotic produces vast quantities of the drug which is converted to the 7-ACA intermediate before being further modified to produce the range of cephalosporins on the market (Wright et al., 2014).