The Mode of Action of Penicillin

Abstract

ALTHOUGH penicillin has been used successfully in clinical medicine for some 20 years its precise mode of action has until recently been ill understood. Now, progress can be reported.Previous reviews on its mode of action have been published by Rinderknecht (1 946), Pratt and Dufrenoy (1 947) and Eagle and Saz (1 955), and Stenlake (1959) has recently summarised the actions of various antibiotics. Because one of the main effects of penicillin appears to be concerned with an inhibition of bacterial cell wall synthesis, the greater part of this review will deal with cell wall structure and the effect thereon of the antibiotic.After this review was completed, a review on the mucopeptide components of bacterial cell walls was published by Work (1961) who described briefly the effect of penicillin on cell wall synthesis. Morphological Changes Induced by PenicillinGardner (1940) reported that, in dilute solutions, penicillin induced a distinct lengthening in all the rod-shaped bacteria which were sensitive to the antibiotic. In a later report, Gardner (1945) extended his work to a microscopical examination of the effect of penicillin on the spores and vegetative cells of bacilli, and found that even the weakest inhibitory dose of penicillin attacked the organism in the early stages of germination. It was also shown that lytic changes in vegetative cells of Bacillus anthracis were less pronounced in a strong than in a weak penicillin solution. Thomas and Levine (1945) demonstrated that penicillin in inhibitory but not completely bacteriostatic concentrations induced bizarre involution forms in Gram-negative intestinal bacteria growing in liquid or solid media. Fisher (1946) showed that the in vitro activity of penicillin on staphylococci caused enlargement of the bacterial cells followed by lysis. Similar effects were observed to a lesser degree on cultures of /3-haemolytic streptococci and pneumococci. Fisher also made the interesting observation that the group A streptococcus was not killed in the same manner, since there was no evidence of debris to suggest that many of the bacteria had been lysed, although cultures were almost sterile after 10 hr. and completely so after 24 hr. Duguid (1946) showed that low concentrations of penicillin induced giant forms in Escherichia coli and Hughes, Kramer and Fleming (1946) described the morphological changes induced by penicillin in Proteus vulgaris; these included (a) elongation up to 200 p in length, and (b) production of single or multiple swellings on the rods. Often, completely spherical, actively motile forms of 6 p or less could be observed on microscopical examination.

Penicillin Induced Lysis in Escherichia coli

“…However, we have found that the activity of soluble RNA seems to be affected (to be published) and this is reasonable, since uridylic and cytidylic compounds accumulate during penicillin action (Strominger, 1960;Saukkonen, 1961) and the re-utilization of these mucleotides may thus be blocked. Several investigators (Prestidge & Pardee, 1957; Hugo & Russell, 1961) have suggested that penicillin may have an additional action beside that of the inhibition of cell-wall synthesis.…”

“…In the extensive literature on penicillin action (see review by Hugo & Russell, 1961) the methods of observation normally used are measurements of viable count, which takes 48 hr., and minimal inhibitory concentration (MIC), which takes 241 hr.…”

“…The inJuence of the medium on the time to lysis Todd (1945) showed that for Gram-positive bacteria ' the most rapid lysis occurs with organisms a t the maximal rate of multiplication', but he could not demonstrate this for 'Bacillus coli'. Since then some conflicting data have been reported (see review by Hugo & Russell, 1961), but it is a general rule that penicillins act only on growing organisms. We studied the time to lysis for Escherichia coli strain x5 in five different media which gave more than a twofold difference in growth rates.…”