E. The Limits of Specificity
IX. THE ORIGIN AND FUNCTION OF ANTIBIOTICS
It is difficult to contemplate the rich variety of antibiotics, and their baroque molecular architecture, without speculating about the functions and evolution of these peculiar compounds. This is a field that has been largely neglected, so that it is much easier to pose questions than to frame answers.
Early investigators had no doubt that antibiotics are agents of chemi-cal warfare, secreted by organisms such as actinomycetes and molds to aid them in the struggle for existence [see, for example, Brock's discus-sion (865) and the quotation from Vuillemin at the head of this chapter].
Evidence in support of this strictly teleonomic view has, however, proved to be elusive. Microorganisms that do not produce antibiotics appear to survive as well in the soil as those that do; indeed, the poten-tial capacity to produce antibiotics is often expressed only under condi-tions that do not obtain in the soil. Moreover, microorganisms elaborate a host of pharmacologically active metabolites—antibiotics, toxins, anesthetics, hallucinogens, and so on—not to mention those that are devoid of any known activity. There is no reason to believe that all these compounds confer a selective advantage on the producer organism in its natural environment. In a sense, then, we ourselves have created the antibiotics by selecting those few compounds of interest to us by virtue of their antimicrobial properties, while ignoring the majority of metabolites that lack useful characteristics (866-869).
Let me point out parenthetically that, even if antibiotics confer no selective advantage on the producer cells, antibiotic resistance is almost certainly an adaptive response. Pollock (370) has argued convincingly that the enzyme penicillinase has served for centuries, at least, to protect
bacteria from the lethal effects of penicillin. The rapid evolution of antibiotic resistance in response to selective pressures is all too dramati-cally demonstrated by the explosive spread of R factors the world over in little more than a decade.
Most investigators today classify the antibiotics among the "second-ary" metabolites, "natural products that have a restricted taxonomic distribution, possess no obvious function in cell growth and are synthe-sized by cells that have stopped dividing" (366). It has been suggested that certain microorganisms, as they approach the stationary phase of growth, accumulate large pools of precursor molecules such as acetate, pyruvate, nucleotides, and amino acids. These are diverted into sec-ondary metabolism lest they become toxic to the cells. Thus the process of secondary metabolism would be of great significance to the
survival of the producing organism, and there is evidence that inter-ference with secondary metabolism may be lethal. However, the products of secondary metabolism would be of no function or significance, except as a special kind of shunt product; any biological activities they may possess would be entirely fortuitous, and their extravagant structures would be intended merely to minimize feedback inhibition of their own accumulation (366-368).
348 F R A N K L I N Μ. HAROLD
But is it really necessary to go so far? Granting that antibiotics were not designed by nature to be antibiotics, must it follow that they serve no function whatever in the producing organism? Attempts have been made to determine whether antibiotics do play a regulatory or structural role under normal conditions; unfortunately, the evidence is meager and indecisive. It has been known for many years that some relationship exists between sporulation and the production of antibiotics by gram-positive bacilli, but it is still unclear whether the antibiotics are neces
sary for sporulation to occur (371). Recent work discounts earlier ideas that bacitracin (372) and polymyxin (373) are components of the spore wall. On the other hand, it appears that streptidine is a component of the cell wall of Streptomyces, both in strains that produce useful quantities of streptomycin and in strains that do not (374) ·
There remains the remote possibility that normal cells contain but a few molecules of the antibiotic, or perhaps of a related compound, which would serve a regulatory or catalytic role. In this sense, it has been considered that actinomycin might be a natural repressor limiting m R N A production (167, 375), while valinomycin may contain clues to the structure of natural K+ carriers in membranes. I know of no solid evidence in favor of this view, but a function involving no more than a few molecules per cell may be hard to detect and even harder to disprove. Yet a serious attempt just may uncover a wholly unsuspected world of biochemical phenomena.
Note added in proof: Since this chapter was written, new data have become available, particularly on antibiotics that affect the synthesis of protein and of nucleic acids. For somewhat more current treatment, readers are referred to the review articles by Pestka (376, 377), Wehrli and Staehelin (378), and by Goldberg and Friedman (879).
ACKNOWLEDGMENTS
I am indebted to Dr. F. B. Rogers for arranging a MEDLARS search of the recent literature and to Ned Eig, Ethel Goren, Nadia de Stackelburg, and Donald Papineau for their help in preparing this chapter for publication. The quotation from P. Vuillemin, translated by the late Professor H. W. Florey (1), is cited by permission of Oxford University Press. Dr. M. J. Hall, Dr. D. Crowfoot Hodgkin, Dr. H. R. Perkins, and Dr. L. K. Steinrauf kindly authorized me to reproduce schemes and drawings from their published work, which appear here by permission of Academic Press and Nature. Dr. B. D. Davis, Dr. S. Omura, Dr. H. R. Perkins, Dr. E. D. Weinberg, Dr. F. L. Weisenborn, and Dr. H. Zahner called my atten
tion to papers which I would otherwise have missed. Errors of omission are
per-haps inevitable in a review of this sort, and I offer my apologies to those whose contributions were overlooked. But when all is said and done, this chapter could never have been written but for the patient and unsung labors of innumerable species of Streptomyces.
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