Antibiotics

The other major breakthrough in the treatment of infectious diseases was of course the discovery of naturally occurring antimicrobial agents, or antibiotics. These are metabolites produced by certain microorganisms, which inhibit the growth of certain other microorganisms. As we shall see, the definition has been extended to include semisynthetic derivatives of these naturally occurring molecules. Table 14.1 lists some commonly used antibiotics.

One of the best known of all stories of scientific discovery is that of how Sir Alexander Fleming discovered penicillin in 1928. Before we consider that, however, it is worth noting that a number of treatments for infectious diseases practised over the preceding

Table 14.1 Some antibiotics and their microbial source

Antibiotic

Microbial Source

Bacteria (Gram-positive)

Bacitracin

Bacillus subtilis

Polymixin

Bacillus polymixa

Actinomycetes

Gentamicin

Micromonospora purpurea

Actinomycin D

Streptomyces parvulus

Erythromycin

Streptomyces erythreus

Streptomyces

Nystatin

Streptomyces noursei

Rifamycin

Streptomyces mediterranet

Streptomycin

Streptomyces griseus

Tetracycline

Streptomyces rimosus

Vancomycin

Streptomyces orientalis

Fungi

Cephalosporins

Cephalosporium acremonium

Griseofulvin

Penicillium griseofulvum

Penicillin

Penicillium chrysogenum

An antibiotic is a mi-crobially produced substance (or a synthetic derivative) that has antimicrobial properties.

Box 14.2 Was Fleming lucky?

In the frequent retelling of the discovery of penicillin, much is made of the role played by chance. It is true that the Pénicillium mould in Fleming'spetri dish was an accidental contaminant, but arguably the real stroke of luck was not so much the fact that the contamination occurred but that it was observed by somebody who immediately recognised its significance.

centuries can, with the benefit of hindsight, be regarded as a form of antibiotic therapy. Many hundreds of years ago for example, the Chinese used mouldy soybean curd in the treatment of boils and South American Indians controlled foot infections by wearing sandals which had become furry with mould! In the late 19th century, Tyndall (see Chapter 13) made the observation that a culture medium cloudy with bacterial growth would clear when mould grew on the surface. Around the same time Pasteur and Joubert demonstrated that cultured anthrax bacilli could be inactivated in the presence of certain other microorganisms from the environment. By the early 1920s the search was on for the isolation of a microbially produced antibacterial agent, and Gratia and Dath isolated a substance from a soil actinomycete which came to be known as actinomycin. However, although potent against a number of pathogens, actinomycin is too toxic to be useful therapeutically.

Fleming was also looking for a naturally occurring antimicrobial agent. On one occasion, he noticed that a plate culture of Staphylococcus aureus had become contaminated by the growth of a mould; around it were clear areas, where the S. aureus did not grow. The mould was subsequently identified as Penicillium notatum. and the substance that had diffused through the agar from it, preventing bacterial growth, became known as penicillin. Further investigation revealed that broth from a culture of the Penicillium mould was inhibitory towards the growth of a number of other Gram-positive pathogens, and remained so even when diluted several hundred times. Critically, when tested on mice, it was, for the most part, harmless.

When it came to purifying the active ingredient and using it in vivo however, a number of problems were encountered. The penicillin proved to be impure, only produced in minute amounts, and unstable in the acid conditions of the stomach, thereby limiting its therapeutic potential. After publishing a few papers on the subject, Fleming ceased work on penicillin and it was left to Howard Florey and Ernst Chain in 1939 to take up the challenge of producing it in sufficient quantities and in a pure enough form for therapeutic use. Early work in Oxford had to continue in the United States because of the German air raids in Britain. The American entry into the Second World War in late 1941 meant that the development of penicillin was awarded war project status, giving it greatly added impetus. As a result of their endeavours, the yield of penicillin rose hugely (see Box 14.3), and in 1945, Fleming, Chain and Florey shared the Nobel Prize for their work.

Other antibiotics were also isolated during this period, most notably streptomycin, isolated by Selman Waksman from Streptomyces griseus, which was to prove so effective against tuberculosis.

In 1942 there was only enough penicillin in the world to treat a few hundred individuals, but by the end of the Second World War production had grown to such an extent that 7 million people a year could be treated. By the mid-1950s, such well-known

Box 14.3 How did Florey and Chain improve the yields of penicillin?

The work of Florey and Chain resulted in pure penicillin being produced on a large scale, suitable for therapeutic use. Among their achievements were:

• isolation of a better penicillin-producing species (P. chrysogenum, famously isolated from a mouldy cantaloupe melon in Peoria Illinois!) and selection of mutant strains induced by X-rays and UV irradiation

• development of submerged culture technique, with sterile air being forced through the medium to supply essential oxygen

• improvements in medium composition

• addition of precursors to the medium

• refinements to recovery methods.

antibiotics as tetracycline, chloramphenicol and neomycin had been isolated. The discovery of a few naturally occurring compounds had revolutionised the treatment of infectious diseases.

New antibiotics are still being sought today; in Chapter 17 we discuss the stages in the isolation, testing and development of a putative new antibiotic. Of the thousands isolated so far, only a small proportion have proved to be of any real therapeutic or commercial value. This is because, like the actinomycin mentioned above, most of the substances isolated harm not only bacteria but humans too.

A key prerequisite for any chemotherapeutic agent is selective toxicity. An obvious way of achieving this is for a compound to direct its effect against a metabolic or physiological function found in microbial cells but not in the host. We shall look at some examples of this later in this chapter. Those chemotherapeutic agents which inhibit the same process in host as in pathogen, or which cause harm to the host in some other way, are said to have side-effects. These may include directly toxic effects, hypersensitivity (allergic) reactions or adverse effects on the host's normal resident microflora.

One of the reasons why penicillin was, and continues to be, so successful, was that the target of its action is unique to bacteria, so it its degree of selective toxicity is high.

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