An antibacterial drug kills or inhibits a bacterium by interfering with some vital process. Any one drug is effective against only some bacterial groups and species, and usually against only some strains of any given species. The remaining bacteria owe their resistance to:
(1) Impenetrability of their outer layers to the drug.
(2) Lack of any important metabolic process to which the drug has any relevance for example sulphonamide resistance due to possession of a dihydrofolic acid reductase which does not 'confuse' sulphonamides with PABA .
(3) Ability to destroy the drug or convert it into an inactive form for example penicillinases (β-lactamases), which open up the β-lactam rings of penicillins and to variable extents also of cephalosporins; or the acetyltransferases by means of which some bacteria can acetylate chloramphenicol. Since the bacteria that produce such enzymes are as a rule intrinsically sensitive to the drug, their resistance may not be manifested when small numbers of them are exposed to an adequate concentration of the drug without being given time to produce enzyme; this is particularly the case when the enzyme is inducible rather than constitutive.
Even when an antibacterial drug is first introduced, the existence of naturally resistant bacterial species and strains places limits on its usefulness. However, there can have been few pathogenic bacteria in circulation 30 years ago which could have survived the onslaught of our present-day armoury of drugs if these had all become available at once. Many of our modern therapeutic problems are due to the fact that in most cases the introduction of a new drug has been followed by proliferation of bacterial strains resistant to it. Staphylococcus aureus has been notably successful in keeping pace with new discoveries. In relation to penicillin it is thought that evolution of new strains has played a relatively small part, the increase in frequency of penicillin-resistant Staphylococcus aureus and other species is largely due to existing resistant strains as their more sensitive colleagues were eliminated. But with most other drugs sensitive strains give rise to rare resistant mutants; these normally have no particular survival value, but in the presence of an appropriate concentration of the drug in question they alone are able to multiply, giving rise to a new strain with increased drug resistance.
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