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
Timing: Allow about 15 minutes
First, listen to the following audio recording about the discovery and development of cephalosporins.
Download this audio clip.Audio player: Audio 1
Transcript: Audio 1 Discovery and development of cephalosporins.
NARRATOR
It may not surprise you to hear that a story which starts knee-deep in sewage will end with the spread of drug-resistant infections like MRSA and c-dif. But this story doesn't take an obvious path, meandering as it does through the history of medicine, along paths paved with the best of intentions, setting the scene for what may be the biggest health challenge mankind has faced since the dawn of medicine. This is the story of cephalosporins, a diverse class of structurally similar antibiotics.
But back to the sewage. As you might imagine, a sewer system is a rich microbial ecosystem, fed with human waste and plenty of water. This gives rise to interesting interactions, where many species fight among the faeces, vying for dominance and continually evolving new ways to stay on top. As a result, the chemical mecanisms developed by some of these species make ideal drug candidates.
In 1948, Italian scientist Giuseppe Brotzu was examining fungal cultures extracted from a sewer in Sardinia. Although penicilin had been discovered twenty years earlier, it only became regularly used to treat infections in 1942. So the idea that fungi could provide useful antibacterial drugs was still relatively new and exciting. He noticed that cultures of the fungus Cephalosporium acremonium supressed the growth of Salmonella typhi, the infectious agent responsible for typhoid, and that a crude filtrate from the fungus could also inhibit the growth of Staphylococcus aureus.
In Oxford, Guy Newton and Edward Abraham, the latter best known for his contribution to the development of penicillin, took the cephalosporin story to the next chapter. They isolated and refined compounds from the culture, removing side chains until they fell upon 7-aninocephalosporic acid, or 7-ACA, the nucleus of
cephalosporins. This, much like 6-aminopenicillanic acid with penicilin acts as the starting block for a host of derivatives, the mother to several generations of drugs. Cefolotin, the first of the cephalosporins to reach the market, was first released in 1964 and continues to be used today.
Along with penicillin, monobactams and carbapenems, cephalosporins sit in a class known as the beta-lactam antibiotics. They share a similar mode of action, inhibiting cell wall development and leading
to cell disruption and lysis. First-generation cephalosporins in common with other early drugs in their class were only really effective against gram-positive bacteria, which includes the bugs modified to increase oral availability and plasma stability, as well as to improve activity against gram-negative bacteria. There are just two drugs in the fifth generation: Ceftobiprole and Ceftaroline. But they account for the only drugs of their type that are effective against methicillin-resistant Staphylococcus-aureus, or MRSA.
So cephalosporins are the drugs that could, but for a score of years, have been penicillin, and Brotzu's name may have been as well known as Flemming's. They've certainly attracted wide use having become a major part of the antibiotic arsenal of most hospitals in developed nations, both as a treatment and a prophylactic to prevent infection post-surgery. But instead of the fame and glory, cephalosporins have attracted critism and are considered by some to be the driving force behind the development of drug-resistant bacteria.
In a 2001 article in the Journal of Antimicrobial Chemotherapy, Stephanie Dancer of the Vale of Leven District Hospital in Dunbartonshire examined the evidence that 'Cephalosporin usage is the most important factor in the selection and propogation of microorganisms, such as Clostridium difficile, methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, multiply resistant coliforms and vancomycin-resistant enterococci, the continuing increase of which threatens the future of antimicrobial therapy.'
Dunbarton goes on to explain that because cephalosporins are effective against a broad spectrum of pathogens, they are often deployed early before lab tests have confirmed the specific cause of an infection. But they're not effective against all common infectious bacteria, and those unaffected therefore have opportunity to overgrow. For known pathogens, this obviously leads to secondary infections, but it can also alter the balance of your microbiota so much that low risk or even friendly bacteria can become a problem - when allowed to overgrow Candida albicans causes yeast infections and Clostridium difficcile, which can exist without issue in the gut for years, can become a killer.
Dunbarton goes on to conclude 'the selection pressure created by heavy usage of cephalosporin antibiotics over the last twenty years has generated a pleathora of multiply-resistant organisms. The risks posed by overuse of cephalosporins remain only speculative, unless specific proof is forthcoming. By then though we may be contemplating the post-antibiotic era.'
So a drug that started its story in a sewer and went on to find glory treating and preventing infection may be one of the causes of two major changes in the history of medicine.
Audio 1 Discovery and development of cephalosporins.
Interactive feature not available in single page view (see it in standard view).
Now answer the following questions, based on the audio recording.
- Who discovered the first cephalosporin?
Interactive feature not available in single page view (see it in standard view).
- What antibacterial activity did a crude extract derived from C. acremonium demonstrate?
Interactive feature not available in single page view (see it in standard view).
- Which chemical structure is described as the ‘nucleus’ of cephalosporins and why is it significant?
Interactive feature not available in single page view (see it in standard view).
- What is the difference between the first and later generations of cephalosporins in terms of their spectrum of activity?
Interactive feature not available in single page view (see it in standard view).
Answer
- The Italian scientist Giuseppe Brotzu (1895–1976).
- The extract could suppress the growth of Salmonella typhi and Staphylococcus aureus.
- The starting point for all cephalosporin derivatives (generations) is 7-aminocephalosporic acid, or 7-ACA.
- 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.
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).