Antimicrobial Agents

Antimicrobial Agents

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, numer-ous derivatives of sulphanilamide were synthesised, many of which were more potent antimicrobial agents than the parent molecule. This class of compounds is known col-lectively as the sulphonamides, or sulfa drugs. 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Nowadays, sulphonamides have largely been replaced by antibiotics because of their side-effects, and because, due to wholesale and indiscriminate use in the early years, bacterial resistance to sulphonamides has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 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 produc-tion of mycolic acid in the mycobacterial cell wall.

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. 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.