Antimicrobial Chemotherapy

Nucleic acid metabolism may be interrupted at many steps. Antibacterial agents show selective toxicity either because humans lack the metabolic processes that act as targets, or because the bacterial targets are much more susceptible to particular chemicals than their eukaryotic counterparts.

Humans are unable to make folic acid, a precursor of purine synthesis. We require an exogenous supply of this metabolite obtained from our diet. Many bacteria are, however, able to generate folic acid from para-amino benzoic acid (PABA) and this pathway provides a target for synthetic antimicrobial agents like the sulphonamides and trimethoprim. Sulphonamides act by inhibition of dihydropteroate synthetase because it acts as a structural analogue of the normal substrate, PABA. Trimethoprim inhibits dihydrofolate reductase, the next step in the folic acid biosynthetic pathway. Trimethoprim was first introduced to be used in combination with sulphonamides to potentiate their activity. Studies of the combination in vitro show that the combination is synergistic. This means that the combined activity of the drugs is more effective than the additive action of the individual components. The synergism observed in vitro, however depends upon maintaining a critical ratio of the two antimicrobials. Because of pharmacological constraints, this cannot be achieved in the body, raising doubts about the synergism in vivo. Furthermore, using two agents for chemotherapy significantly increases the risk of the patient developing an adverse reaction to the treatment. Such arguments led to the introduction and successful use of trimethoprim as a single agent.

Chemical structure of para-aminobenzoic acid

Chemical structure of sulphamethoxazole,
a sulphonamide

Chemical structure of trimethoprim

Bacterial DNA exists in a supercoiled form and the enzyme DNA gyrase, a topoisomerase, is responsible for introducing negative supercoils into the structure. Quinolone antibacterial drugs such as nalidixic acid, norfloxacin, ofloxacin and ciprofloxacin act by inhibiting the activity of the bacterial DNA gyrase, preventing the normal functioning of DNA. Humans do possess DNA gyrase but it is structurally distinct from the bacterial enzyme and remains unaffected by the activity of quinolones. These are broad-spectrum agents that rapidly kill bacteria and are well absorbed after oral administration. Overuse of these drugs in certain situations is selecting quinolone resistant mutants and these may threaten the long term use of such compounds.

Chemical structure of nalidixic acid

Chemical structure of ciprofloxacin