René Dubos, a Harbinger of Microbial Resistance to Antibiotics

RENEDUBOS, A HARBINGER OF MICROBIAL RESISTANCE TO ANTIBIOTICS CAROL L. MOBERG* To regard any form of Ufe merely as slave orfoe will one day be considered poor philosophy, for all living things constitute an integral part of the cosmic order.—René Dubos, 1901-1982. [1] As early as 1942, microbiologist René Dubos predicted that bacterial resistance to antibiotics should be expected: In the analysis of the mode of action of antibacterial agents, it may be profitable to keep in mind that susceptible bacterial species often give rise by "training" to variants endowed with great resistance to these agents. In some cases, drug resistance may be due to changes in metabolic behavior. . . . [or] may result from a change in cell permeability. [2] One rather startling aspect of this first warning of an impending crisis in medicine is how early it appeared in the antibiotic era. Two new antibacterial substances—penicillin and Dubos's own gramicidin—werejust emerging from laboratory research. These antibiotics were in the first stages of clinical trials and not yet available for general Use. The gold rush for other antibiotics had not even begun when Dubos also warned that searching for more was not enough. Instead, his plea was directed toward finding more accurate knowledge of "synthetic processes of the microbial cell" and thereby obtaining highly specific ways to control bacterial growth. Another surprising aspect ofthis prediction is that it predates the science of molecular biology. In 1942, questions were still unanswered about whether bacteria had genes and whether DNA was the genetic material. While modern bacterial genetics has since developed much knowledge concerning molecular mechanisms of antibiotic resistance, Dubos based his This paper is extracted from a book in preparation about René Dubos. The author is grateful for the interest and assistance received from Rollin Hotchkiss, Alexander Tomasz, David Thaler, Brace Levin, Frederick Seitz, and Ralph Steinman. Reprinted with permission from Microbial Drug Resistance, Vol. 2, No. 3, Fall 1996. *The Rockefeller University, 1230 York Avenue, New York, NY 10021. 0031-5982/99/4203-1108$01.00 Perspectives in Biology and Medicine, 42, 4 ¦ Summer 1999 | 559 prediction on 20 years of research experience with ecological facets of bacterial adaptations. His observations of the interplay between organisms and their environments, whether in soil, laboratory cultures, or animal tissues, formed his broad knowledge of natural variability, plasticity, and antagonisms among microbial populations. This work led him to systematically develop an antibiotic of his own in 1939. By the time he issued his prediction three years later, bacterial resistance to gramicidin had been found and confirmed by other researchers. A further surprise, today, is that Dubos's perspective was neither particularly original nor alarming to medical scientists of that era. In the half century before antibiotics, the number of clinically useful drugs was limited (vitamins, a few hormones including insulin, arsenicals, and sulfonamides), and sporadic reports of resistance were considered negligible. However, the rapidity and magnitude with which antibiotics were introduced after 1942 set the stage for a large-scale problem with fatal consequences. In this regard, Dubos was timely and prescient in expecting "great resistance." This prediction was the first of many issued by Dubos over the following 40 years. Once he grasped that bacterial resistance should be expected, he set about to probe deeper and to anticipate consequences of this phenomenon . One result was that he continued to predict that antibiotics, along with the increasing array of chemical therapies, could treat and control acute cases, but they could never eliminate infectious diseases. Also, his continuing work led to ever-broadening views of bacteria, hosts, and environmental changes. Based on his experiences, Dubos envisioned what could be called medical microbial ecology, where alternative approaches to infectious diseases would work with rather than fight against bacteria. Scientific Background ofDubos's Prediction The roots of Dubos's first warning on antibiotic resistance were grounded in abundant research concerning bacterial responses to external factors. What he found was an extraordinary plasticity of bacteria to adapt themselves amidst the constant warfare in microbial milieus. He observed that some bacterial responses are reversible while others are transmitted to succeeding generations. Today's discussions of drug resistance and bacterial genetics focus on concepts of...