Antibiotics in Action

Antibiotics in Action

LEADING ARTICLES 1031 devise critical experiments to show which of the interactions between bacterium and drug is of real importance and whether the...

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devise critical experiments to show which of the interactions between bacterium and drug is of real importance and whether the; resultant modifications of bacterial metabolism affect the organism directly or indirectly. SMITH s named forty-nine bacterial metabolic processes and enzyme systems which have been studied for their sensitivity to chloramphenicol, but he considered that only two of these were clearly

significant as causes of growth inhibition-namely, interference with utilisation of amino-acids and with the metabolism of fats and esters. He cited work by GALE and PAINE 7which suggests that chloram-




Antibiotics in Action REVIEWING problems affecting the search for microorganisms that produce antibiotics, ROUTIEN and FINLAY1 forecast that unsolved problems will continue to attract research-workers to this subject. A satisfactory agent against the smaller viruses has not yet been discovered ; possibly an antibiotic might be useful in the treatment of cancer ; and better agents against mycobacteria and protozoa

much needed. The resources of industrial firms well organised and skilfully directed in the search, which seems for the present to be largely concentrated on the rewarding genus streptomyces. Many programmes of systematic exploration are being undertaken, chiefly on a great variety of soils from all parts of the world but also on such varied material as growing plants, culture collections, waters, muds, bogs, composts, decaying leaves, earthworms from graveyards, sewage, fermentations, and anthills. Studies have been made, too, of bacteria from human infections undergoing resolution,2 and there have been attempts to induce antibiotic-producing mutants among micro-organisms by X-ray and ultraviolet irradiation. The search for new antibiotics is largely empirical ; and individual workers with few resources should not be discouraged, for an acute observer whose mind is prepared and whose approach is flexible may still hope to meet and recognise one of the lucky chances which have so often led to great discoveries. are


Empirical methods, however, are not enough. important developments of chemotherapy have naturally been followed by. explanations of the properties of antibiotics in terms of their chemical reactions with living matter. Speculation and The

research on this topic began with EHRLICH’S sidechain theory, and new reports continue to appear at short intervals. Since we last commented on this 4 much of the recent knowledge has been subject reviewed in a symposium arranged by the Society of


B’acteriologists.5 Clearly, many different biological properties of bacteria are affected by some of the antibiotics,

1. Routien,

and it is


difficult to

J. B., Finlay, A. C. Bact. Rev. 16, 51. 2. Rountree, P. M., Barbour, R. G. H. 1952, J. Path. Bact. 1951, 63, 313. 3. Kelner, A. J. Bact. 1949, 57, 73. 4. Leading article, Lancet, 1952, ii, 374. 5. Bact. Rev. 1953, 17, 17.

may possibly act by inhibiting protein synthesis, because of its action in preventing the formation of combined glutamate and the utilisation of ammonia. An important point about chloramphenicol inhibition of esterase activity is that this action is found with esterases isolated from tissue cells as well as with bacterial esterases, but that intact tissue cells-of horse-liver, for examplepossess a mechanism which prevents the antibiotic from inhibiting the esterase activity of the host cells. HOBBY,8reviewing work on aureomycin and terramycin, mentioned evidence for their action on the phosphorylation system, on the metabolism of tricarboxylic acids and fx-ketoglutarate, and on the oxidation of glycine, glutamic acid, and aspartic acid. She referred to AJL’S9 view that the actions of terramycin and aureomycin are similar, and that the site of their action may involve the initial step in acetic-acid oxidation. The hypothesis that antibiotics stimulate animal growth simply by inhibiting intestinal organisms is now in some doubt, because growth responses have been observed with doses of antibiotics which are too small to act on the intestinal flora ; it appears that the drugs may act by increasing absorption of nutrients as well as by inhibiting drugsensitive pathogens. OGINSKY,10 discussing the mode of action of streptomycin, drew attention to its inhibition of aspartate and amino-acid oxidation by Bacterium coli, and to other respiratory effects causing increased acetate formation. In bacterial cells capable of oxidising acetate, no streptomycin inhibition of the oxidation of pyruvate and oxalacetate could be demonstrated, but the oxidation of these substrates was much inhibited if acetate oxidation was slight or absent. Studies of the action of streptomycin on the tubercle bacillus indicated that the oxidation of the longchain fatty acids is sensitive to the drug, but that oxidation of the short-chain fatty acids is not, suggesting that their metabolism by the organism may also be different. PRATT 11 drew attention to changes in the morphology and staining reactions of penicillin-treated organisms. These changes are the same as those described by STEARN and STEARN 12 as characteristic of starving bacteria," which fits in with the knowledge that penicillin prevents staphylococci from absorbing glutamic acid and various inorganic substances and generally interferes with the ability of "

6. Smith, G. N. Ibid, p. 19. 7. Gale, E. F., Paine, T. F. Biochem. J. 1950, 47, xxvi; 1951, 48, 298. 8. Hobby, G. L. Bact. Rev. 1953, 17, 29. 9. Ajl, S. J. Unpublished data. 10. Oginsky, E. L. Bact. Rev. 1953, 17, 37. 11. Pratt, R. Ibid, p. 41. J. Bact. 1930, 20, 287. 12. Steam, A. E., Steam, E. W.


1032 _

substances as lipoids, nucleotides. It appears and cobra venom exert on similar actions bacteria ; and this supports many the idea that penicillin may interfere with the phosphorylation of important nucleotides and that its effect on bacteria may depend on excessive dehydrogenation of reduced substances-probably those bearing sulphydryl groups. If these assumptions are correct, penicillin will be most effective at a concentration which accelerates the transfer of hydrogen from -SH or other reduced groups without seriously hindering the activity of hydrogen acceptors. On this basis it would be expected that the most efficient and rapid antibacterial effects would follow the use of the least concentration capable of producing irreversible injury to the -bacteria. At an appropriate lower concentration than the optimum, penicillin might be expected to act as a growth stimulant, and at concentrations much higher than the optimum the drug might so impair the activity of hydrogen acceptors as to give some protection to the hydrogen donors against the rapid, irreversible dehydrogenation There is clinical on which its action may depend. and experimental evidence for the view that bacteria are less efficiently killed by concentrations of penicillin and other antibiotics above and below the optimum.13 Isoniazid has not yet been so intensively studied as the other antibiotics, but an explanation of its mode of action might be particularly interesting since it is active only against mycobacteria. BARCLAY et al.,14 using isoniazid labelled with C14, studied the uptake of drug and its effect on bacterial growth in a normal culture and in a culture of a drugresistant variant of the same strain of Mycobacterium tuberculosis (H37RV). Isoniazid did not halt growth immediately ; the tubercle bacilli continued to multiply, at first quite rapidly, but then more and more slowly until growth ceased at a point when the bacterial population had approximately doubled. The isoniazid effect was not influenced bacterial numbers or phase of growth, or by changes in concentration of drug within the range 0.05—100 µg. per ml. The organisms whose growth was arrested retained some enzyme activity and were neither killed nor lysed. Those subjected to low concentrations of drug resumed growth in about two weeks and were then resistant to the concentration of drug in the medium. All this contrasted strikingly with the effects of streptomycin, which arrested growth almost at once, stopped enzyme activity, killed the organisms, and led to perceptible lysis of the culture in three Resistant organisms eventually appeared, days. however, and growth was resumed. The radioactive isoniazid clearly showed that the sensitive strain of bacteria took up the drug, whereas the resistant strain did not. Isoniazid action thus has points in with sulphonamide action, which may common that absorption of the drug interferes with suggest the formation of an essential metabolite. Reviewing problems of combined chemotherapy, GARROD 15 has declared that we still do not know enough about the mode of action of antibiotics to

explain with certainty why the use of two drugs helps to prevent the development of resistant bacteria. Probably the second drug blocks the metabolic pathway developed by a resistant organism to circumvent the effect of the first drug. Since so many combinations of drugs are effective in this way, GARROD suggests that by studying their effects it may be possible to discover more about the points of attack of individual drugs. Clearly, a great deal of laboratory work lies ahead. Some of this, as GARROD points out, will be extremely laborious-work on a

organisms to retain such fatty-acid hydrolysates, and that penicillin, ribonuclease,


13. Gould, J. C., Bowie, J. H., Cameron, J. D. S. Lancet, Feb. 21, 1953, p. 361. See also leading article, Ibid, March 7, 1953, p. 475. 14. Barclay, W. R., Ebert, R. H., Koch-Weser, D. Amer. Rev. Tuberc. 1953, 67, 490. 15. Garrod, L. P. Brit. med. J. May 2, 1953, p. 953.

of enterococcal endocarditis which he studied occupied well over 100 hours of laboratory timeand much of the work, as WYcs 16 has said, resembles groping in the dark. Nevertheless the recent contributions show that we have a considerable body of new knowledge about the biochemistry’and physiology case



Children in Road Accidents OUR predecessors fenced off those dangerous trains, and forbade the public to invade the permanent way. Motor-cars do not run at fixed times, do not announce their approach as noisily as trains, and are just as dangerous to life and limb ; yet we all share the same roads-young and old, halt and spry, motorists, cyclists, and pedestrians alike-and we look like doing so for the rest of this century. Road-accident figures are so monotonously high that those who wish to sting us into some sense of responsibility have to use devices to touch the imaginationtelling us, for example, that on our roads during 1951 at least one child was killed or injured in every This fact alone should make us fifteen minutes. demand to know the ages of the children, and what they were doing at the time ; and an important study 17 along these lines has just been published by the Economic Research Council for the Children’s Safety Crusade Trust, founded by the late Mr. GORDON STEWART. The trust have presented their report to the National Federation of Women’s Institutes, who gave them substantial help in deciding on age-span groupings of children, and offered many opinions which the subsequent analysis of figures proved to be shrewd and sound. With Prof. HARRY JoNES as chairman, the study group 18 have discussed their findings in terms of risk-rates." These are calculated to represent the risk of injury per 10 million children per day within each age-group, and are therefore strictly comparable: thus, if the risk-rate of a 12-year-old boy on a June schoolday is 20, and that of a 4-year-old on a similar day is 150, the risk to the younger boy is 71/2 times greater than the risk to the elder. The study group have taken it that a risk-rate of 20 (the average risk of a child as passenger on the road) is probably as "


Wyss, O. Bact. Rev. 1953, 17, 17. 17. The Child on the Road. Economic Research Council, 18, South Street, London, W.1. Pp. 70. 4s. 18. The members were : Prof. J. HARRY JONES, LL.D., author of Report on Road Accidents for the Ministry of Transport in 1946; Miss ENID BLYTON, author of books for children; Lieut.-Colonel G. T. BENNETT, M.I.C.E., and Mr. ERIC FARMER, M.A., both members of the Road Research Board ; Mr. G. PRYS WILLIAMS, F.I.S., economist and statistician; and Mr. HAROLD S. GOODWIN, secretary of the Economic Research Council.