Origin and Function of Penicillinase: A Problem in Biochemical Evolution

Abstract

The enzyme, generally known as “penicillinase,” that hydro-lyses the /3-lactam bond of penicillins and cephalosporins, with production of the antibiotically inactive penicilloic and cephalo-sporoic acids, exists in a number of different forms, produced by a wide range of Gram-positive and Gram-negative bacterial genera (Bacillus, Staphylococcus, Escherichia, Klebsiella, etc.). Despite some striking chemical and biological differences, there are probably significant resemblances between most of the varieties of penicillinase that have been studied in purified preparations. This supports the hypothesis of a common or closely related evolutionary origin. The restricted specificity and high detoxifying activity of most penicillinases suggest that their physiological functions and evolutionary pathways are specifically related to the antibacterial action of the penicillins and cephalosporins. Moreover, the production of these antibiotics is more widespread among soil and dermatophytic microfungi than is commonly supposed, and the natural distribution of penicillin-producing micro-organisms seems to correspond fairly closely to that of penicillinase-producers. The recent demonstration of significant penicillin production by Penicillium growing in soil unsupplemented by “artificial” nutrients suggests that previous scepticism regarding formation of the antibiotic “in nature” may not be justified, and that the penicillin/penicillinase relationship may be of importance in soil ecology. Consideration of the evolutionary origin of penicillinase remains highly speculative, though it is clear that the various forms of the enzyme, as we now know them, pre-existed the therapeutic penicillin era, the only effect of which, in this context, has been to increase by natural selection the proportion of bacteria producing them. Search for a possible penicillinase-ancestor is focused on the only other known class of protein that must, on a priori reasoning, be capable of specific combination with penicillin—that is, one or other of the enzymes involved in biosynthesis of the mucopeptide of the bacterial cell wall, a reaction known to be specifically inhibited by this antibiotic. © 1967, British Medical Journal Publishing Group. All rights reserved.