In Chapter 1, we saw how by the end of the 19th century, the germ theory of infectious diseases had finally gained widespread acceptance. It is hardly surprising then, that the scientific community at that time should turn its collective mind towards ways of controlling infections and the organisms that cause them. In the following pages we shall discover how the development of chemical agents targeted against pathogenic microorganisms had a dramatic impact on the treatment of infectious diseases in the twentieth century.
The term chemotherapy is most closely associated in the minds of most people with the treatment of cancer. In fact the term was first used by Paul Ehrlich to describe any use of a drug or other chemical substance for the treatment of disease; thus, it has much wider terms of reference. In our present discussion, we shall confine ourselves to chemotherapy as it relates to the treatment of infectious diseases. It was Ehrlich who, 100 years ago, observed how certain dyes would stain bacteria but not the surrounding tissues, leading him to formulate the idea of selective toxicity, whereby a substance would selectively target harmful microorganisms but leave human tissues undamaged. He tested hundreds of synthetic compounds in the search for his 'magic bullet' before finding, in 1910, an arsenic-containing drug, Salvarsan, which was effective against Treponema pallidum, the causative agent of syphilis (Figure 14.1).
It was another 20 years before another significant antimicrobial drug was developed, when the German chemist Gerhard Domagk showed a synthetic dye, Prontosil, to be active against a range of Gram-positive bacteria. The active component of prontosil was shown soon afterwards to be sulphanilamide. In the following decade, numerous derivatives of sulphanilamide were synthesised, many of which were more potent antimicrobial agents than the parent molecule. This class of compounds is known collectively as the sulphonamides, or sulfa drugs (Box 14.1). In the years leading up to the Second World War, sulphonamides dramatically improved the mortality rates due to pneumonia and puerperal fever.
Nowadays, sulphonamides have largely been replaced by antibiotics because of their side-effects, and because, due to wholesale and indiscriminate use in the early years, bacterial resistance to sulphonamides has become widespread. Some synthetic compounds are still useful as antimicrobial agents, however. Isoniazid is one of the principal agents used in the treatment of tuberculosis. It
A side-effect is an undesirable and unintended effect of a therapeutic treatment on the recipient.
Box 14.1 Sulphonamides - the deadly mimics
Sulphonamides exert their effect by fooling the bacterial cell into thinking they are molecules of p-aminobenzoic acid (PABA) because of their similar structures (see below).
PABA is a precursor of folic acid, which is required by cells as a coenzyme in the synthesis of nucleic acids. The sulphonamide acts as a competitive enzyme inhibitor (see Chapter 6), preventing the synthesis of folic acid, which in turn affects nucleic acid metabolism and leads to cell death. Because of their close structural resemblance to the PABA, the sulphonamides are said to be structural analogues; another, equally descriptive name is antimetabolites.
is nearly always given in association with another antimicrobial agent because of the high incidence of resistant forms of the mycobacteria that cause the disease. Like the sulphonamides, isoniazid is a structural analogue, and is thought to inhibit the production of mycolic acid in the mycobacterial cell wall (see Chapter 7).
The quinolones are synthetic substances related to nalidixic acid, and include ciprofloxacin and norfloxacin. They interfere with nucleic acid synthesis by inhibiting DNA gyrase, the enzyme responsible for unwinding DNA prior to replication (Chapter 11). Quinolones are used in the treatment of urinary infections, as are the nitrofurans. These are active against certain fungi and protozoans as well as a range of bacteria.
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